CONFERENCE COVERAGE SERIES
International Conference on Alzheimer's Disease 2002
Stockholm, Sweden
20 – 25 July 2002
Stockholm: Visualizing Amyloid Biggest Draw at Imaging Symposium, Consensus Sought on Validation
On day one of the 8th International Conference on Alzheimer’s Disease and Related Disorders, held from July 20 to 25 in Sweden’s magnificent capital, the Alzheimer’s Imaging Consortium hosted a one-day symposium that highlighted recent advances in using MRI, SPECT and PET to aid in the diagnosis of AD as well as the assessment of experimental therapies.
Organized by Michael Weiner of the University of California, San Francisco, the symposium attracted well over 100 scientists. The talks ranged from imaging amyloid plaques in humans, early detection of AD by measuring the shrinkage of particular brain areas, to the role of functional MRI, longitudinal imaging studies, and other topics. Two things stood out. One was a presentation of new radioligands that can label amyloid plaques in humans and animals, the other was an attempt by the research community to reach a consensus on where AD imaging research should go next to validate the diverse research approaches and channel them towards clinical applications.
First, the news. Following a talk by Jorge Barrio of University of California, Los Angeles, (see ARF related news story). William Klunk of the University of Pittsburgh, Pennsylvania, presented new data of his attempt, together with Chester Mathis and collaborators in Boston and Uppsala, to develop a PET imaging agent that can quantify amyloid plaques in live humans. In addition to providing a pathological diagnosis, such an agent could track the success of clinical trials testing experimental therapies to lower amyloid deposition. Klunk introduced a thioflavin derivative called BTA-1, and reported that it fulfills all of the criteria needed to move such compounds into human trials: It binds amyloid with high affinity and high specificity, it readily crosses the blood-brain-barrier, but also clears rapidly. It is non-toxic and works well in transgenic mice.
Demonstrating BTA-1 action in PSAPP transgenic mice, Klunk’s collaborator Brian Bacskai in Brad Hyman’s group at Massachusetts General Hospital in Boston, Massachusetts, will present on Monday a movie made from multiphoton microscopy images, showing how the compound crosses the blood-brain barrier and, within 30 minutes, labels existing plaques from the outside in. Klunk previewed the movie in this talk.
The moment of truth, however, is the human study, he added. On Tuesday, Mathis will detail how BTA-1 compared in uptake and clearance with currently used PET tracers. And on Wednesday, Henry Engler of Uppsala University in Sweden will present results of a first, small human trial. In people with early AD, BTA-1 labeled frontal and temporoparietal association cortices, the anterior and posterior cingulated cortices and the caudate, all areas known to contain plaques. (PET cannot resolve individual plaques, that is part of why the scientists test this compound with multiphoton microscopy in mice). In the five controls, non-specific labeling washed out rapidly, leaving a clear separation between cases and controls, said Mathis. Next, the scientists want to test the compound in patients with even earlier stages of cognitive impairment, to see how amyloid load correlates with progression to AD. Klunk and Mathis are negotiating an agreement with a pharmaceutical company interested in marketing BTA-1 as a therapy-monitoring marker for SPECT.
In the ensuing discussion of amyloid imaging approaches, Steve Younkin of the Mayo Clinic in Jacksonville, Florida, said that radioligands will probably turn out to be safe and may be useful in conjunction with drug trials. However, he expects this method to remain too costly for use in routine diagnosis, and noted some knotty problems in validating it. How, for example, could one determine the variation in the signal obtained from two people with the same amyloid burden? Finally, Younkin cautioned that the increasing realization about soluble Aβ assemblies being as or even more toxic than fibrillar deposits might weaken the utility of this technique, should it turn out that soluble and fibrillar Aβ do not correlate.
Next, the consensus. This symposium also saw the beginning of emerging agreement among imaging researchers on how to move current research toward the clinic. The Imaging Working Group sponsored by the Alzheimer Association has over the past months solicited the views of scientists in this area, and some of those presented consensus statements aimed to direct programmatic and policy issues. Weiner, who chairs the working group, said that the group will soon formalize the consensus statements and submit them to the Alzheimer Association. But even as draft statements were introduced briefly at the end of today’s session, the consensus appeared fragile: Several members of the audience asked why SPECT imaging had been omitted from consideration, and urged the working group to consider this technology, which is widely available at many medical centers.
This news summary of the symposium does not include all 23 research presentations. Selected highlights included a talk by Marilyn Albert of Massachusetts General Hospital, in which she described MRI and SPECT studies to define which sorts of measurements best enable a prediction of who will convert from “questionable” to overt AD. The goal is to pick up selective changes in the brain that distinguish those who have normal age-related memory lapses from those with incipient AD. Studying a cohort of 123 people with a diagnosis of questionable AD and 42 controls who have been followed for several years, Albert has published previously that the entorhinal cortex shrunk in volume as people progressed from control status. The hippocampus also shrunk, but not until the subjects clearly had mild AD. To improve the accuracy of this prediction, Albert and colleagues included size measurements of the banks of the superior temporal sulcus and the anterior cingulate.
To address the most clinically important question, namely who of those with a “questionable” diagnosis will convert to AD, Albert et al. combined MRI and SPECT data. In unpublished work, they measured a total of nine regions of interest and used new SPECT quantification methods. This improved the prediction’s accuracy to 99 percent overall, and to 86 percent in that most difficult category. “This is much better than what a skilled neurologist could do,” she said.
In a similar study of 113 people with mild cognitive impairment (MCI) or clinical AD plus controls, Corina Pennanen of Kuopio University Hospital in Finland described MRI measurements revealing that entorhinal cortex volume is a better discriminator than hippocampal volume between controls and people with MRI. However, hippocampal volume better than entorhinal cortex volume distinguishes people with AD from controls and from those with MCI, suggesting that the hippocampus degenerates a bit later as the disease progresses. Over all, most talks echoed the finding that the entorhinal cortex heralds the earliest detectable changes, but that the hippocampus follows closely behind. This begins to settle the debate in the literature about whether morphometric measurements of the hippocampus were suitable in imaging early AD, says Albert.
Gene Alexander of Arizona State University in Tempe, used voxel-based MRI to measure how gray matter shrunk in cognitively normal people with one or two copies of the ApoE 4 allele. Previous work had shown that ApoE4 carriers show reduced glucose metabolism and greater declines in metabolism than those with the E2 or E3 alleles of this AD risk factor. Studying a group of 36 cognitively normal adults by imaging them once at baseline and then once again two years later, they found significant declines in certain brain regions of E4 carriers even though these people did not have any detectable cognitive decline. Homozygotes had a steeper decline than did heterozygotes for E4. E4 homozygotes also had greater degrees of whole brain atrophy than E2 or E3 carriers. Since all these findings are presymptomatic, this approach could eventually be used for diagnosis, said Alexander.
Mony de Leon of New York School of Medicine described a biomarker combination approach, in which hippocampal volume measurements together with CSF and plasma measurements of phosphorylated tau improved the specificity and sensitivity of either test alone. The combination did not, however, improve the clinical diagnosis. Gunhild Waldemar at Copenhagen University Hospital dampened the general enthusiasm, saying that the added value of these imaging approaches to a clinician’s daily practice will remain low as long as data analysis is non-standardized, control material is sometimes of poor quality, and the quality of the instruments varies greatly. She said that in her practice, volumetric measurements or other biomarkers offer real value only for a small minority of patients, such as middle-aged people with mild memory loss.
Scott Small of Columbia University described MRI studies in mouse models, asking whether MRI could pinpoint the lesion within the hippocampus inflicted by overexpressed AβPP. He showed that the CA3, CA1 areas change most between non-transgenic and transgenic mice. In normal aging, by contrast, the subiculum changes the most, confirming a previously found difference between normal aging and AD.—Gabrielle Strobel
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Stockholm: Chlamydia Triggers Amyloid Plaques in Mice
Stockholm. Chlamydia pneumoniae is an insidious intracellular bacterium to which almost the entire worldwide population has been exposed by age 70. It primarily causes inflammatory lung disease but has in the past decade been implicated in the development of atherosclerotic plaques. Yesterday at the 8th International Conference on Alzheimer’s Disease and Related Disorders, Brian Balin and colleagues at the Philadelphia College of Osteopathic Medicine presented data showing that chlamydia isolated from Alzheimer’s brain, cultured, and then sprayed into the noses of young wild-type BALB/c mice can cause progressive deposition of amyloid plaques, in essence creating a partial model of AD without using any transgenes. At 15 months, plaque load rises steeply, Balin said.
“We believe this could be a trigger mechanism for the pathology in AD,” said Balin. “People have been suspecting this for decades but could not find anything. It is very difficult to pinpoint an infectious cause for a progressive, chronic disease. We also believe that our isolation of chlamydia from the human AD brain and induction of pathology in normal mice is proof of principle that this can be a causative mechanism turning on pathology.”
Balin and colleagues identified the plaques with Aβ42 antibodies and thioflavin-S staining. They have not found neurofibrillary tangles in their mice, but are currently looking for tau accumulation and neuritic dystrophy in older animals. They also have not yet looked for behavioral deficits.
Interestingly, Balin and his colleagues found the bacterium primarily in microglia, astroglia, and perivascular macrophages, both in human and the mice. A poster on Wednesday examines pathways by which this organism can enter the brain after a respiratory tract infection, essentially suggesting that blood monocytes harboring the pathogen can penetrate the blood-brain barrier by altering tight junctions. Balin believes that chlamydia, which is known to upregulate the expression of proinflammatory cytokines, may induce amyloid pathology as a consequence of this glia-derived inflammation.
In 1998, these researchers reported in Medical Microbioloy and Immunology that of 50 brains of sporadic AD cases, 90 percent had chlamydia in their brains, whereas only five percent of the controls did. Since exposure is widespread, this begs the question which genetic host response factors may allow some people to shed the infection more effectively than others. These could be among genetic risk factors for some cases of sporadic AD, said Balin. For a start, Alan Hudson and colleagues at Wayne State University School of Medicine in Detroit, Michigan, tomorrow are presenting data suggesting that cultured human astrocytes are more easily infected with chlamydia if they are ApoE4 positive than if they carry the other ApoE alleles, and that ApoE4-positive samples of frontal and temporal cortex and hippocampus of AD brains had higher bacterial load than did samples carrying E2 or E3.—Gabrielle Strobel
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- Gérard HC, Wang GF, Balin BJ, Schumacher HR, Hudson AP. Frequency of apolipoprotein E (APOE) allele types in patients with Chlamydia-associated arthritis and other arthritides. Microb Pathog. 1999 Jan;26(1):35-43. PubMed.
- Balin BJ, Appelt DM. Role of infection in Alzheimer's disease. J Am Osteopath Assoc. 2001 Dec;101(12 Suppl Pt 1):S1-6. PubMed.
- Balin BJ, Gérard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, Whittum-Hudson JA, Hudson AP. Identification and localization of Chlamydia pneumoniae in the Alzheimer's brain. Med Microbiol Immunol. 1998 Jun;187(1):23-42. PubMed.
Stockholm: Aph-1 and Pen-2: New Names in the Presenilin Debate Complete the Complex?
Stockholm. One of the unresolved issues in the debate about γ-secretase revolves around the other members of the complex besides presenilin and nicastrin. If they were all isolated and better understood, it might be possible to reconstitute γ-secretase activity in vitro, a definitive experiment to prove the identity of γ-secretase.
A poster and a talk at the 8th International Conference on Alzheimer’s Disease and Related Disorders today presented new information on other protein members of the presenilin complex. The poster, by Jinhe Li at Pharmacia Corporation in Kalamzoo, Michigan, and colleagues there and at Exelixis Inc. in South San Francisco, described how C. elegans-based genetic screens for presenilin enhancers yielded three genes (aph-1, aph-2/nicastrin, and pen-2) that are required for presenilin function in Notch cleavage. The authors cloned the human homologs (aph-1a, aph-1b) and report that they are broadly expressed in different tissues. They also mapped aph-1a, pen-2 and nicastrin to chromosome regions reported to probably harbor AD risk genes. The work appeared in the July Developmental Cell.
The researchers used yeast two-hybrid assays and co-immunoprecipitation to detect interactions between aph-1b, pen-2, nicastrin , and presenilin 1. Aph-1, aph-1b and nicastrin appeared to reside in the ER in a pattern that resembles previous PS-1 localization studies. The poster proposes a complex consisting of presenilin, aph-1a, aph-1b, aph-2/nicastrin, and pen2. To test whether these new proteins can modulate Aβ generation, the scientists transfected HEK293 cells with aph-1a, aph-1b, and pen-2 versions bearing small deletions or substitutions and showed that these alterations affected Aβ levels.
Finally, the poster showed on nicastrin/pen-2 double knockout mice, showing they are embryonic lethal in much the same way as are presenilin1/2-double knockout mice, presumably due to impaired notch signaling.
As likely members of the γ-secretase complex, aph-1a, aph-1b, and pen-2 could be targets for drug development, the authors write, even as additional biological targets for γ-secretase keep emerging.
Working with Dennis Selkoe, Michael Wolfe, and others, Taylor Kimberly of Brigham and Women’s Hospital expanded these findings to his work with Chinese hamster ovary cells. Kimberly reported today that when overexpressing all three, aph-1, pen-2, and presenilin-1, γ-secretase activity shoots up in extracts of these cells when he added the substrate. In parallel, the authors saw increased generation of both Aβ and AICD, the intracellular cytoplasmic fragment of APP. (Nicastrin was already present in excess quantities in these cells.) “With these two additional components in hand, I now believe the γ-secretase complex is complete. We can now try to reconstitute activity in vitro,” said Selkoe.—Gabrielle Strobel
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Stockholm: Clusterin (or Beware the Evil Chaperone!)
Stockholm. Injecting a fresh set of data into the debate about what is toxic and why-fibrillar amyloid or early, oligomeric forms of Aβ-scientists at the 8th International Conference on Alzheimer’s Disease and Related Disorders today presented their work on clusterin, an Aβ binding protein also called ApoJ. The study appears today in the Proceedings of the National Academy of Sciences.
Ron DeMattos, David Holtzman and colleagues of Washington University, St. Louis, with others at Eli Lilly and Co. and at University of Cincinnati College of Medicine, took earlier in vitro work on interactions between clusterin and Aβ in vivo by breeding PDAPP mice with a clusterin knockout strain.
They found that mice overproducing Aβ but lacking clusterin accumulated and deposited as much amyloid as did mice that had clusterin. However, the amyloid was different. The clusterin-free PDAPP mice had fewer fibrillar deposits and altered pools of soluble Aβ. At the same time, they showed markedly less neuritic dystrophy around the sites of amyloid deposition in their brains. This finding uncouples amyloid deposition from neurotoxicity and points a finger at an intriguing protein that modifies the formation of toxic amyloid species. ApoE and ApoJ/clusterin are the two most abundant apolipoproteins in the brain.
With clusterin, a larger proportion of Aβ converted to thioflavine-S positive fibrillar amyloid than without clusterin. How could it work? This remains unclear, but DeMattos et al. suggest that clusterin might promote the formation of toxic oligomeric forms of Aβ, as previous in vitro studies have suggested.
It is unclear how clusterin’s observed effect of changing soluble Aβ pools in vivo relates to its other observed effect of modifying fibrillization in a way that increases toxicity. An emerging literature is beginning to describe clusterin as a secreted chaperone, which can solubilize different proteins that have in common that they expose hydrophobic sites. Perhaps chaperone-like interactions between clusterin and Aβ change the equilibrium between soluble and deposited Aβ, the authors speculate. This could unmask epitopes that increase toxicity to neurites, either on soluble Aβ or on fibrillar amyloid.—Gabrielle Strobel
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Stockholm: Gold in Them Thar Hills?
Stockholm. In the early days of the California gold rush, it looked like all you had to do to join the ranks of the rich and famous was to pack up a mule, stake a claim, and start picking up the nuggets. But apart from a limited number of rich veins discovered by a few lucky individuals, finding and harvesting those riches turned out to be hard work and, for most folks, unsuccessful. Might the same thing be in store for genetic miners working on Alzheimer’s disease?
Many investigators would trace the advent of “modern” AD research to the discovery of genetic mutations associated with familial forms of the disease. These well-established loci are associated with three genes, APP, PS1 and PS2. The fact that virtually all of the mutations result in elevation of Aß42 levels has bolstered the “amyloid cascade” hypothesis (reviewed by John Hardy in one of the plenary talks here), which, in spite of ongoing modification, still places the Aß peptide as central to disease etiology. The nagging doubts that continue to plague some investigators regarding this virtual dogma arise from the fact these mutations occur in a remarkably small number of families and, according to most estimates, probably account for, at most, five percent of AD cases. Yet the success of the gene-screening approach in identifying potential causes of familial forms of the disease has spurred continued effort to locate comparable genetic risk factors for the so-called “non-familial” or sporadic forms of the disease, most of which have a later age of onset (LOAD).
Virtually every Alzheimer’s conference has an obligatory session devoted to the latest progress in the search for these genes, and the international conference in Stockholm is no exception. Several such reports were presented from this apparently limitless frontier by leaders of the search, several of whom have already earned their place in the miners' Hall of Fame. The details of the reports presented at this session might make fascinating yarns to those who truly grasp concepts such as Markov Chain Monte Carlo simulation methods and SNP haplotype analysis. However, to to the rest of us, the bottom line is whether or not specific genes are implicated in AD risk. It probably is premature to say that the search should be called off, but the take-home message may not be too different from the quip that Rudy Tanzi offered when his Powerpoint slides initially failed to appear on the screen. “There aren’t any more Alzheimer’s genes,” he announced. “Thank you. Any questions?” The resulting laughter from the audience was genuine, but seemed to carry a note of anxiety. This is not to say that the list of candidates has gotten any shorter. The territory is still expansive and a number of loci across several chromosomes (1, 5, 6, 9, 10, 12, 19 and 21) have been inconsistently reported to show linkage to AD. But an association comparable to what appears to now be the gold standard of ApoE, remains to be detected.
The panel of speakers included Christine Van Broeckhoven, Gerry Schellenberg, Rudy Tanzi, Lannfelt, Alison Goate and Peggy Pericak-Vance, a stellar lineup of seasoned miners to be sure. And they all seem to agree that there is still gold in “them thar hills” and that “candidate” genes are likely to exist on chromosomes 10 (Goate, Pericak-Vance, Tanzi), 12 (Schellenberg) and 19 (Schellenberg, apparently at a different site than ApoE). On chromosome 10, insulin degrading enzyme (IDE), is a contender and is consistent with other recent lines of evidence indicating that this enzyme may be an important regulator of Aß levels (Tanzi). But Goate noted that none of the candidates they have looked at on chromosome 10, including IDE, have survived scrutiny. (In fact, data to be presented later at this meeting by Steve Younkin suggest that the locus on chromosome 10 may be a gene for an α-catenin that might have a role in presenilin function.) A large scale study of SNPs on chromosome 9 (Pericak-Vance, Schellenberg) have also failed to identify clear leads but the Pericak-Vance group did find some evidence for disease risk associated with specific mitochrondrial haplotypes. Schellenberg provided evidence for a hot spot on chromosome 19 that is distinct from ApoE. So at this time, chromosomes 10 and 19 appear to harbor relevant genetic loci for the risk of late-onset AD but there is no consensus on the identity of the genes.
Each speaker made cases for particular gene candidates, but it seemed clear that no new El Dorado has been identified. One question that none of the speakers addressed is whether it would ever be possible to know when to call off the search (by the way, there are still places in California where you can pan for gold). Certainly, the difficulty now facing this talented group of genetic sleuths is the establishment of the boundaries of the search. Is there a minimal LOD score that can be reliably used to identify relevant genes? Are negative results ever definitive? Tanzi made the point, for example, that the linkage to chromosome 12 is not especially strong, but that their haplotype analysis still implicates α-2-macroglobulin (a still controversial candidate for AD risk). This is just one indication of the difficulty facing further mining in this harsh genetic landscape. But if new genes are to be found, these seasoned prospectors are likely to find them.—Keith Crutcher
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Stockholm: Not All NSAIDs Are Equally Good When it Comes to Alzheimer’s
Stockholm. Today at the 8th International Conference on Alzheimer’s Disease and Related Disorders, Monique Breteler and colleagues at Erasmus Medical Center in Rotterdam, Netherlands, reported the surprising result of a reanalysis of their previous paper, which had sparked controversy (see related news item, see NSAID discussion transcript). Last fall, Bas In’t Veld et al. reported that NSAID consumption protected against AD, and that this applied to all NSAIDs that were taken by the 7,983 study participants of their community-based cohort. Shortly thereafter, Sascha Weggen et al. reported in Nature that, in vitro, the NSAIDs ibuprofen, indomethacin, and sulindac, but not naproxen or diclofenac, work by lowering Aβ42 production. This triggered debate about whether the experimental data was applicable to human AD, and about which NSAIDs would work in clinical treatment trials.
Prompted by the Weggen et al. paper, Breteler then reanalyzed their data by grouping the Aβ42-lowering and non-lowering NSAIDs in separate groups. Their poster showed that the protective effect they previously reported for all NSAIDs lumped together is actually restricted mostly to those that lowered Aβ in the Weggen et al. experiments. The adjusted risk ratio for ibuprofen, indomethacin, and sulindac decreased down to 0.62 depending on how long study participants took the drugs. However, the adjusted risk ratio for diclofenac and naproxen remained around one. “Our reanalysis agrees completely with the Weggen et al. data,” said Breteler. The data is not yet published.—Gabrielle Strobel
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- in t' Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. N Engl J Med. 2001 Nov 22;345(21):1515-21. PubMed.
- Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001 Nov 8;414(6860):212-6. PubMed.
Stockholm: Separating Good from Bad Inflammation in AD: Complement Steps into Limelight
Stockholm. The complement cascade is a series of consecutively activated proteases that, somewhat like the caspases, culminates in a powerful protein assembly that eventually kills any cell against which it is directed. In a presentation yesterday at the International 8th International Conference on Alzheimer’s Disease and Related Disorders in Stockholm, researchers found a role for this cascade in AD by showing that AβPP transgenic mice bred to lack a key component needed to rev up the complement exhibit widespread neurodegeneration (a feature curiously missing from most current mouse partial AD models) as well as increased amyloid plaque formation.
This is interesting for several reasons. First, it gives researchers a new handle on understanding the emerging question whether part of the inflammation widely observed in AD might be beneficial by helping to remove amyloid. Second, it may help to understand the activation process of microglia. While known to engulf and clear away plaque when properly activated, this small, quasi-immune glial cell has nevertheless proved elusive and difficult to study.
More generally, the study continues to broaden the range of functions, both good and bad, that have begun to emerge for the complement cascade in recent years. Originally discovered as part of the first line of defense against bacteria, the complement is now known to be an indispensable step in the activation of mast cells, but also to figure in the pathogenesis of the autoimmune disease lupus erythematosus, in asthma, and in reperfusion injury, a serious problem in surgical practice.
Tony Wyss-Coray at the University of California, San Francisco, and coworkers elsewhere, showed a poster that also appears in the PNAS early edition this week. The study continued previous work showing that AβPP transgenic mice that were also overproducing the proinflammatory cytokine TGF-1β had activated microglia and less Aβ accumulation than mice transgenic only for AβPP. What, however, was mediating this activation? A hint existed in that these APP/TGF-1β mice had elevated levels of C3, a central step in complement activation.
Wyss-Coray and colleagues then bred PDAPP mice with mice transgenic for the natural complement inhibitor Crry, originally made by co-author Richard Quigg at the University of Chicago. At 10 months, these mice had higher Aβ levels in neocortex and hippocampus, more plaques and altered Aβ turnover. At the same age, complement-deficient mice had 50 percent fewer neurons in the CA3 subfield of the hippocampus, which is known to degenerate early in human AD, while three-month old mice did not yet have this cell loss. Neuritic dystrophy was widespread but the microglia, meanwhile, were less activated in the AβPP/Crry mice.
The complement has previously been shown to be involved in AD. It is upregulated in AD, and aggregated Aβ can activate it in vitro. This study takes previous work in vivo.—Gabrielle Strobel
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Stockholm: Larger Study Finds Protective Effect of Statin Use
Stockholm. Today at the 8th International Conference on Alzheimer’s Disease and Related Disorders, Robert Green of Boston University School of Public Health presented another piece of evidence in the story of statin use to prevent or treat Alzheimer’s disease. Two previous reports have hinted that people who take statins to lower their plasma cholesterol might be at lower risk for cognitive decline, but researchers agree these papers need to be followed up by larger studies.
Green presented unpublished data of a new analysis of an observational, family-based case-control study of 2,378 people at 15 research centers, the first epidemiological investigation of statin in AD to include significant numbers of African American subjects. This is the largest epidemiological study of statins in AD to date, Green said.
Green, Lindsay Farrer, and colleagues found that family members of patients with AD who took statins had a 39 percent lower risk of developing AD than those not on statin. Interestingly, cholesterol-lowering agents other than statins did not show this association, suggesting that at least part of the apparent effect of statin on cognition is mediated through the drug’s inflammatory and perhaps other functions.—Gabrielle Strobel
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Stockholm: Liver Found to Degrade Aβ
Stockholm. A growing line of investigation in Alzheimer’s research suggests that the Aβ peptide produced in the brain is transported into the periphery on a routine basis, and that this transport chain, whatever its precise mechanism, could perhaps be exploited for therapy one day by “drawing” Aβ out of the brain. One simple but unanswered question here is what happens to peripheral, circulating Aβ. This is important to know not just for future therapeutic applications but also for a better understanding of how Aβ gets turned over during a person’s many decades of healthy life prior to the onset of AD. How does the body dispose of it normally, and why is it accumulating only in the brain, not in the periphery?
On Monday, Miguel Calero, working with Jorge Ghiso and others at New York University School of Medicine, presented a poster here at the 8th International Conference on Alzheimer’s Disease and Related Disorders that revealed some of the pharmacokinetics of soluble Aβ40 and 42. Calero et al. radiolabeled Aβ with a sugar that allows cells to take up circulating serum Aβ into their lysosomes but then traps it there because the lysosomes cannot degrade the sugar. They injected this once into the tail vein of mice and checked which organs had taken up most of the Aβ at several time points up to 10 hours later.
The researchers found that the liver accounted for 60 percent of the total peptide uptake (followed by the kidney), with 87 percent of that stuck in hepatocytes, not other cell types in the liver. Some labeling was in the gall bladder and small intestine, suggesting that it is being excreted via bile. This finding fuels the--largely speculative-notion that Aβ buildup in the LOAD brain could, at least in part, result from a problem in the liver, essentially causing a backup at the source as transport and peripheral clearance gradually fail due to age-related decline.—Gabrielle Strobel
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Stockholm: Bad News Official: The Rofecoxib and Naproxen Clinical Trial Has Failed
Stockholm. This morning at the 8th International Conference on Alzheimer’s Disease and Related Disorders, Paul Aisen of Georgetown University Medical Center in Washington confirmed the whispers that had been going around among the AD community for a while: The treatment trial of the two NSAIDs naproxen and rofecoxib has not shown any benefit in any of the endpoints measured.
The trial was run by the Alzheimer’s Disease Cooperative Study (ADCS), a multicenter consortium conducting clinical trials of various experimental therapeutics. An ADCS trial of the cholesterol-lowing agent simvastatin, for example, is expected to begin this fall.
The rofecoxib/naproxen trial is the latest in a small number of NSAID trials and followed on the heels of a trial of the steroid drug prednisone, which had also failed. The trial was designed based on evidence that inhibiting the cox 1 and/or 2 enzymes, which are expressed in AD brain, might slow the inflammatory changes that accompany AD. Naproxen is a mixed cox1/2 inhibitor; rofecoxib is one of the newer selective Cox2 inhibitors and was chosen because it promised to be safer for chronic use and because Cox2 is upregulated in AD neurons. Even that did not really pan out, however: 23 percent of the 351 enrolled patients with mild or moderate AD dropped out, mostly because of gastrointestinal side effects.
The trial evaluated success by looking for changes, after one year on drug, in the ADAScog rating scale. It also assessed other cognitive, clinical, and behavioral measures and endpoints such as death, institutionalization. Patients showed no real improvement in any of these measures, those taking rofecoxib even worsened a bit, though that was not statistically significant.
This disheartening result is no surprise to those researchers who believe that only certain NSAIDs, but not rofecoxib and naproxen, inhibit presenilin and that this is a key mechanism of NSAID action in AD. (There are several other proposed mechanisms for how NSAIDs work in AD, however.) The trial failure is also consistent with the reanalysis of the epidemiological data from the Rotterdam study reported here yesterday (see story below).
Finally, ADCS currently conducts a prevention trial for AD using naproxen and celecoxib. Celecoxib is a cox-2 inhibitor much like rofecoxib, raising questions about whether the latest epidemiological and in vitro research still supports this choice of drug.—Gabrielle Strobel
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Stockholm: Presenting α-T Catenin: A Long-Awaited Gene on Chromosome 10?
Stockholm. Perhaps the hottest buzz at the 8th International Conference on Alzheimer’s Disease and Related Disorders here in the City of Water revolved around a candidate gene rumored to have finally been found on chromosome 10, the genome area that several genetics labs have scoured ever since reports about a probable linkage to late-onset AD (LOAD) appeared about it in 2000. This morning, Nilufer Ertekin-Taner in Steven Younkin’s lab presented unpublished data suggesting that α-T catenin was at least one of the AD-linked genes in this region. The work is based on the analysis of 10 extended families of LOAD patients who had extremely high plasma Aβ42 levels.
α-T catenin is an effective binding partner of β-catenin, which is known to interact with presenilin-1, Ertekin-Taner said. It also resides at the 80 centimorgan address that the group had previously found to be most strongly linked to LOAD.
The Younkin team then looked for single nucleotide polymorphisms (SNPs) and found one, the T allele of 4360, that appeared to be associated with elevated Aβ42 levels. The 4360 SNP resides in an intron, raising the question how it could possibly affect Aβ42 levels. In her presentation, Ertekin-Taner said her data led her to suggest the working hypothesis that SNP causes a splicing change that leads to the translation of a truncated, dysfunctional protein.
The researchers also studied a large case-control series to see if they could find associations with the 4360 SNP, and apparently it came up positive only when linked to ApoE. As is usually the case when a research team proposes a new gene for AD, this work will surely be hotly debated while the other laboratories in the field try to reproduce the data. Ertekin-Taner said that she suspects the relevant region on chromosome 10 to contain additional AD genes, particularly upstream of α-T catenin.—Gabrielle Strobel
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Stockholm: Educated Guessing Game: Which Genes Does “Other” APP Snippet Regulate?
Stockholm. Last July, Thomas Sudhof created a buzz in the Alzheimer’s research community when he reported elegant in vitro work suggesting that the C-terminal fragment of AβPP (APPct), the poorly understood second product of γ-secretase cleavage, could enter the nucleus and change gene expression there (see related news item). Here at the 8th International Conference on Alzheimer’s Disease and Related Disorders in Stockholm, Paul Coleman and his colleagues at the University of Rochester, as well as other labs, presented work carrying this clue further.
On Monday, first author Min Zhu presented a poster describing immunohistochemistry of neurons in selected brain regions of postmortem samples from people with AD. The antibody detected the APPct, but not the amino-terminal end, in the nuclei. Its amount correlated to disease status and to how vulnerable that particular brain area is known to be in AD. In a second experiment, the researchers cloned APPct and its binding partner Fe65 into green fluorescent protein vectors and transfected mammalian cells. The poster showed that both proteins co-localize in the nucleus.
The answer to the obvious question-which genes are affected by APPct-mediated transcription-remains elusive. Finding out which genes are differentially expressed in the cotransfected cells clearly is the next experiment, Coleman said, but previous work by his and other groups already suggests some candidates that could be tested. For example, a paper in press in Neurobiology of Disease details microarray and RT-PCR studies of gene expression differences between brain tissue of normally aged versus AD brains. It shows that genes related to trafficking of synaptic vesicles have reduced expression very early in AD, at stages when genes related to synaptic structure are still expressed at normal levels. An example is dynamin, a protein involved in retrograde vesicle transport. Its RNA and protein levels decrease steeply in early AD, while levels of the structural marker PSD95 are still normal. Intriguingly, this affects only the respective isoforms of these proteins that handle synaptic vesicle traffic, not those dealing with trafficking around the Golgi and related organelles in the cell body, Coleman added.
Today, Stavros Therianos in Coleman’s lab is presenting a poster about another class of potential candidate genes, namely developmentally regulated genes that are reexpressed in AD. The general concept that AD might represent a regression to an earlier stage originated about 20 years ago, when Peter Davies first showed that the Alz50 antibody was immunoreactive with neurons not only in AD but also in very early embryonic stages. Since then, other genes have been found to be re-expressed in early AD, notably those that regulate the cell cycle (see cell cycle live chat). Yesterday, Yan Yang and Karl Herrup of Case Western Reserve University in Cleveland, Ohio, presented data showing expression of several cell-cycle genes that were reexpressed in hippocampal brain samples of people who had died with a diagnosis of mild cognitive impairment but not cognitively normal controls. Today’s poster by Therianos et al. presented a new set of homeobox genes that are normally expressed only in hindbrain development. Candidates aplenty, but the link to APPct is still up for grabs.—Gabrielle Strobel
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- Cao X, Südhof TC. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001 Jul 6;293(5527):115-20. PubMed.
Stockholm: Could a Whiff of NAP Nip Brain Inflammation in the Bud?
Stockholm. Last Sunday at the 8th International Conference on Alzheimer’s Disease and Related Disorders here, Illana Gozes presented a poster with the latest data in her investigation of NAP. This intriguing peptide of eight amino acids lies within a glia-derived protein called activity-dependent neuroprotective protein, ADNP, which Gozes et al. first cloned in 1999. NAP protects neurons in vitro at femtomolar concentrations, said Gozes. Most currently prescribed drugs work in the nanomolar range at best. Gozes, who is at Tel Aviv University, did this work in collaboration with Douglas Brenneman at the National Institutes of Health in Bethesda, Maryland.
Studies published prior to the international conference in Stockholm showed that NAP is neuroprotective in different in-vitro systems against a variety of toxins, including Aβ, excitotocity, and gp120 of the HIV virus. NAP protects against oxidative stress by increasing glutathione levels in neurons, said Gozes. In a previous study, Gozes and colleagues rescued cultured cells that were dying following pre-treatment with a glutathione inhibitor. NAP also inhibits cell death following hydroxyperoxide treatment, and in 2000, the scientists reported glutathione increase and neuroprotection in a NAP-treated mouse model of severe oxidative stress, Gozes said.
At the Stockholm conference, Gozes et al. reported a preventive in-vivo inflammation experiment that was not specific to AD but is relevant to neurodegeneration. The scientists injected newborn mouse pups daily with NAP for three weeks, and at four months of age inflicted a head trauma, widely seen as a risk factor for dementia. NAP-treated mice recovered faster, and a five-day Morris water maze experiment with the injured mice showed that only those pre-treated with NAP found the submerged platform. In addition, NAP-treated mice had decreased mRNA levels of the inflammatory marker Mac-1. Alternatively, injecting a single dose of NAP 15 hours after injury into mice that had not received it postnatally also kept Mac-1 expression low, Gozes said.
Last April, Gozes and her colleagues published that NAP is neuroprotective in a rat model of stroke when injected four hours after the insult. And last year, they reported that administering NAP through the nose protected mice into whose cerebral ventricles the researchers had previously injected a toxin that slowly kills cholinergic neurons. The researchers again saw a difference in water maze performance.
"In the toxicology we have done until now, we found no side effects, though we still need to do pharmacokinetic and other studies," said Gozes. In general, peptides make poor drugs because they are degraded by proteases and do not penetrate their target cells sufficiently well at safe concentrations. Gozes said, however, that this peptide is unusually stable and appears to penetrate the brain well when administered intranasally. No clinical trial is imminent, though the ADCS in San Diego is considering the approach. Even if all went smoothly in future trials, (which is rare), this peptide would take years before becoming widely available.—Gabrielle Strobel
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- Zemlyak I, Furman S, Brenneman DE, Gozes I. A novel peptide prevents death in enriched neuronal cultures. Regul Pept. 2000 Dec 22;96(1-2):39-43. PubMed.
- Gozes I, Brenneman DE. A new concept in the pharmacology of neuroprotection. J Mol Neurosci. 2000 Feb-Apr;14(1-2):61-8. PubMed.
Stockholm: There Is No Spatial Paradox!
In a wide-ranging and eloquent presentation at the 8th International Conference on Alzheimer’s Disease and Related Disorders held last week in Stockholm, Christian Haass (Abstract 1059) provided several experimental proofs that a small amount of presenilin is detected at the plasma membrane. Using a relatively new technique, total internal reflection microscopy (TIRM) Haass demonstrated that exogenous GFP-tagged PS could readily be detected in the endoplasmic reticulum and also on the plasma membrane. Furthermore, he was able to biotinylate mature Nicastrin on the plasma membrane and then in co-immunoprecipitation experiments he detected endogenous PS heterodimers associated with the biotinylated Nicastrin, thus indicating that two essential components of the γ-secretase complex, namely PS and Nicastrin, are detected together at the cell surface. Based on these experiments, Haass estimated that approximately one-thirtieth of total cellular PS was localized to the plasma membrane.
Haass also presented data demonstrating that Notch and CD44 are cleaved in a PS-dependent manner at a γ-site in the middle of the transmembrane domain at a position equivalent to cleavage after residue 40 of the A β sequence. This cleavage, which he termed site 4 (S4), gives rise to a p3-like, soluble peptide of both Notch and CD44. In addition, he also reported on the well-characterized site 3 (S3) cleavage of Notch detecting a secreted peptide Mass ~4358 consistent with proteolysis just 3 amino acid residues into the transmembrane sequence.
Finally, Haass reviewed data that AβPP was cleaved at a position similar to the Notch S3, aka the ε site, and that familial Alzheimer's disease mutations in PS cause an increase in γ-cleaved APP and Notch and a decrease in ε cleavage. This latter point was corroborated by another speaker, Peter St. George-Hyslop and further suggests that increased production of Aβ is the initiating event in AD pathogenesis as opposed to transcriptional deregulation mediated by an increase in functional AICD generation.
From the data presented it is not possible to determine whether cleavage at the γ and ε sites occur sequentially or simultaneously. In addition to the products discussed above, APPC59, AAβ49 and the 9 amino acid peptide spanning the γ and ε cleavage sites have yet to be detected. Only when these fragments and their temporal production is uncovered will it be possible to determine the order of the γ and ε cleavages.—Dominic Walsh
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- Craft S, Asthana S, Schellenberg G, Baker L, Cherrier M, Boyt AA, Martins RN, Raskind M, Peskind E, Plymate S. Insulin effects on glucose metabolism, memory, and plasma amyloid precursor protein in Alzheimer's disease differ according to apolipoprotein-E genotype. Ann N Y Acad Sci. 2000 Apr;903:222-8. PubMed.
Stockholm: The Presenilin Signaling Hub—A RIP-off or the Real Deal?
Ever since Cao and Sudhof (Science 2001 293, 115-120) provided the first evidence that the intracellular domain of APP (AICD) translocates to the nucleus and may be involved in transcriptional regulation, there has been a reawakening of interest in APP function. Thus, it was appropriate that one of the most thought provoking presentations of the entire meeting addressed this important issue. Breaking from his published abstract Bruce Yankner (Abstract 1061) spoke to the role of presenilin-mediated regulated intramembrane proteolysis (RIP) in cell signaling.
Using Affymetrix gene chips, Yankner and colleagues compared the transcriptional profile of wild type and PS1/PS2 double knockout embryonic stem (ES) cells. Given the dramatic effect of the PS double knockout, it was perhaps not surprising that the gene expression profile of double KO ES cells was substantially different from wild-type ES cells. Indeed, one percent of the total genes detected were altered in the double knockout ES cells.
Mindful of the burgeoning list of putative γ-secretase substrates (see below) Yankner further refined his analysis to attribute the observed changes to the two best characterized γ-secretase substrates, APP and Notch. Cells were transfected with constructs encoding an AICD-like fragment (the C-terminal 59 amino acids of APP) or NICD, RNA extracted and transcriptional profiles determined as before. Interestingly only seven genes were rescued by AICD: the kinesin receptor, Follistatin, TGFβ induced early growth response, caspase 7, Calbindin, Fragile X, and a novel gene product PRT. Of these the kinesin receptor (see Kamal et al. Nature 2002) and the calcium-binding protein Calbindin are particularly interesting. At the Elan satellite symposium on 22 July, Lennart Mucke also reported that Calbindin was elevated in AβPP transgenic mice. PRT, a novel gene cloned from ESTs with homology to the tetraspanins, was markedly increased in PS double knockout ES cells and elevated in ES cells treated with inhibitors of γ-secretase. The tetraspanins are inhibitors of metasis, involved in cell migration and synapse formation, and tetraspanin Kal1 has been shown to be directly activated by a ternary complex containing AICD (Baek et al. 2002 Cell 110, 55-67).
As one would predict based on knockout models of AβPP and Notch, transfection of ES cells with NICD recovered a substantially larger number of genes than the handful of genes rescued by AICD, with many of the NICD-rescued genes acting to stimulate cell migration. In addition, a third set of genes (including APOE and PrP) were altered in the PS double knockout cells but were not recovered by either AICD or NICD.
Although gene array analysis is still fraught with difficulties, and notwithstanding caveats about certain technical aspects of the reported study, the innovative approach of identifying transcriptional targets by comparison of PS double KO cells with wild type or ICD-rescued cells should aid in the identification of the gene targets regulated by ICDs of the various γ-secretase substrates.-Dominic M. Walsh, Ph.D. (Harvard Institutes of Medicine)
Putative Substrates for PS/γ-secretase
1. Erb4 (Todd Golde #549)
2. LRP*
3. APLP1 and 2*
4. Syndecan 3 (Bart DeStrooper #1043)**
5. CD44 (Kwang-Mook Jung & Tae-Wan Kim #782; Sven Laminch & C. Haass, have detected p3-like peptides #1059)**
6. Notch (Okochi & C. Haass, have detected p3-like peptides, #1059)
7. E-Cadherin (Robakis et al. #2079)
8. Delta/Jagged (Sisodia # 1572; LaVoie & Selkoe abstract# 658)**
9. Nectin 1 (Dora Kovacs #532)**
* These proteins were mentioned as γ -secretase substrates by several speakers but to my knowledge have yet to be confirmed.
** Novel presentation at this meeting.
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Paper Citations
- Cao X, Südhof TC. A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60. Science. 2001 Jul 6;293(5527):115-20. PubMed.
- Kamal A, Almenar-Queralt A, LeBlanc JF, Roberts EA, Goldstein LS. Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature. 2001 Dec 6;414(6864):643-8. PubMed.
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Stockholm: Degradation on the Rise
(Meeting report by Malcolm Leissring, Harvard Medical School.) With the exception of Down's syndrome and rare, familial forms of Alzheimer’s, there is little evidence that AD is attributable to overproduction of the Aβ peptide. Therefore, deficits in the proteolytic degradation or clearance of Aβ may be the driving force behind the cerebral accumulation in many-possibly even most-cases of AD (for a recent review, see Selkoe, 2001). In a clear sign of the growing interest in this area, several talks at the 8th International Conference on Alzheimer’s Disease and Related Disorders in Stockholm focused on the biology of two Aβ-degrading enzymes, insulin-degrading enzyme (IDE) and neprilysin (NEP).
Dennis Selkoe (Abstract 552) presented the first evidence that defects in IDE can lead to accumulation of the Aβ peptide in vivo. The work, led by Wes Farris and colleagues, focused on a novel animal model of type 2 diabetes which harbors naturally occurring mutations in IDE. Known as the GK rat model, these animals were developed through a breeding strategy that selected for animals that performed poorly in glucose-tolerance tests. Subsequent genetic analysis by researchers at the Karolinska Institute in Sweden revealed that the diabetic phenotype was associated with two missense mutations in IDE (H18R and A890V).
Selkoe reported that GK rats showed a significant ~15-30 percent defect in the degradation of exogenously introduced Aβ in soluble brain fractions as well as in NaCO3-washed membrane fractions and intact primary fibroblasts. Significantly, primary neuronal cultures from these animals accumulated approximately 55 percent more endogenous Aβ1-40 and ~100 percent more Aβ1-42 in the conditioned medium than in control cultures. The finding that a small (~20-30 percent) decrement in IDE-mediated degradation can lead to such a large (~50-100 percent) increase in Aβ accumulation implies that IDE plays an important endogenous role in the regulation of brain Aβ.
Consistent with this, Selkoe reported preliminary data from a collaboration with Suzanne Guénette and Rudy Tanzi showing that brain Aβ levels are elevated in IDE knockout mice. Elsewhere in the Stockholm conference, evidence of genetic linkage between IDE and late-onset AD was reported by several sources, including Rudy Tanzi (Abstract 1206) and Anthony Brookes (Abstract 1557), suggesting that we will be hearing more about IDE in the years to come.
The next speaker, Takaomi Saido (Abstract 553), reported on his continuing studies of neprilysin (NEP), another Aβ -degrading protease. In the brains of APP23 transgenic mice crossed with NEP heterozygous (+/-) knockout mice, Saido observed a 50 percent increase in Aβ levels. Surprisingly, insoluble Aβ levels in these mice were unchanged, and the increase in overall Aβ was attributable to an approximately two-fold increase in soluble Aβ levels. This finding suggests that different Aβ -degrading proteases may act preferentially on different pools of Aβ . NEP mRNA levels were also reported to decrease with age, and this decrement was associated with particular brain regions (e.g., CA3, terminal zones of perforant path and entorhinal cortex), suggesting that NEP deficiency may play a role in the age-associated increase in the risk of AD.
In degradation assays comparing wild-type Aβ to several intra-Aβ mutants, Saido’s group found that each of the mutants was degraded significantly more slowly by NEP, suggesting that decreased degradation may play a role in certain familial AD cases. Saido also reported significant genetic linkage between AD and a SNP located 159 nucleotides past the stop codon of the NEP gene on chromosome 3. Finally, Saido described a model on which the NEP transript might be regulated by a ligand-receptor system. Using an activity-staining approach, Saido identified somatostatin as a ligand that upregulates NEP levels and proposed ligand supplementation therapy as a novel therapeutic approach to AD.
Roger Nitsch (Abstract 554) rounded out the trio of talks focused on Aβ -degradation. Nitsch reported that NEP mRNA and protein levels were significantly elevated in Aβ PP transgenic mice for as long as 30 weeks following a single intracranial injection of Aβ 1-42. The rise in NEP levels was associated with the prevention of plaque formation and reduced astrogliosis. This surprising result contrasts curiously with his previously reported finding that intracranial Aβ injection causes increased hyperphosphorylation of tau--in the former case Aβ seems therapeutic, while in the latter it appears pathogenic. Perhaps mice doubly transgenic for Aβ PP and tau will be capable of settling the issue.
It should be noted that IDE and NEP are by no means the only proteases implicated in the degradation of Aβ. Genetic and biochemical evidence continues to suggest a role for other proteases such as endothelin-converting enzyme (Abstract 669) and plasmin and its proteolytic activators. In my opinion, the abundance of Aβ -degrading proteases-rather than representing an Achilles’ heel-provides a wide-ranging and nuanced palette of drug targets that may one day allow us to modulate specific pools of Aβ. Judging from the range of data presented at the Stockholm conference, the future looks bright for Aβ-degradation research.
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- Selkoe DJ. Clearing the brain's amyloid cobwebs. Neuron. 2001 Oct 25;32(2):177-80. PubMed.
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- Selkoe DJ. Clearing the brain's amyloid cobwebs. Neuron. 2001 Oct 25;32(2):177-80. PubMed.
Stockholm: Core Resistance
(Report from the World Alzheimer Congress by Keith Crutcher, Ph.D., University of Cincinnati.) A number of strategies are being pursued to treat Alzheimer’s on the assumption that it is primarily a disease of amyloid. One of the most innovative ideas is to immunize AD patients with fibrillar amyloid (thought to be the major component of senile plaques). The failed Elan trial, based on this strategy, has been reported in little detail, primarily through the lay press, so it is hard to know whether the failure was due to undesired side effects of the immunization protocol or whether the vaccine “worked”, leading to negative consequences as a result of successful clearance of plaques. (See related news..)
Certainly there is ample evidence that amyloid can be cleared from the brains of transgenic mice using this approach. But how easy will it be to clear plaques from the AD brain? In the symposium on amyloid-lowering strategies, Dennis Dickson presented a unique and clever approach to addressing the likelihood that macrophage-mediated clearance of amyloid will be an effective strategy in humans. It is known that damage to the brain, such as occurs with cerebral infarcts (strokes), leads to an inflammatory response that includes the activation of microglial cells that clear away the dead tissue. What would happen to plaques and tangles caught in such an infarct where phagocytic activity is heightened?
The examination of such regions in AD brains revealed a clear answer. Although diffuse amyloid deposits and the diffuse halo surrounding dense core plaques appear to be cleared from the tissue, the plaque cores remain. Neurofibrillary pathology also appears to persist in the region of infarcts. This in spite of evidence for IgG immunoreactivity associated with the plaques. So at least under this natural experiment of enhanced phagocytic activity, the culprits implicated in the original formulation of the amyloid hypothesis (fibrillar amyloid deposits) seem to survive what is otherwise a thorough cleaning up operation.
Dickson also described results from animal studies in which doubly transgenic mice (bearing plaques and tangles) were immunized with Aβ42, not unlike the Elan clinical trial. As expected, the immunization protocol prevented plaque formation. In addition, there was some dimunition of the tau pathology in the brain stem and amygdala, but not in the spinal cord. Dickson concluded that immunization with Aβ may have an effect on preventing amyloid deposition but is unlikely to have much effect on the neurofibrillary pathology (which is more relevant clinically according to some).
During the discussion, Dennis Selkoe, who was moderating the session and is perhaps the leading spokesman of the amyloid hypothesis, noted that there is little amyloid in the spinal cord of these transgenic mice, so that there is at least some correlation between the immunization effect on amyloid and tau pathology. Dickson agreed, noting that it might be an issue of seeing the glass as half full rather than half empty. Dale Schenk, credited with the idea of using immunization as a therapy, noted from the floor that they “clearly, definitely, absolutely” see loss of dense core plaques in their immunized mice. Dickson didn’t dispute this but noted that his conclusions about phagocyte-resistant plaques were based on human material. Schenk countered that they could see phagocytosis of human plaques in ex vivo tissue sections, to which Dickson responded that perhaps there would soon be data from the human trial to address this question. The exchange highlighted the continuing uncertainty and, some would say, secrecy surrounding the vaccine trials. But until autopsy material becomes available, the extent to which immunization results in loss of amyloid plaques in humans remains an open question.
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Stockholm: Pictures at an Exhibition
(Report from the World Alzheimer Congress by Keith Crutcher, Ph.D., University of Cincinnati.) In the early days of optical astronomy the resulting images were fuzzy at best, and even into the early part of the last century astronomers were often drawing conclusions based on less than ideal images. (Lowell’s fabulous descriptions of the canals on Mars and the implications for Martian civilization come to mind.) A similar situation confronts the modern day neuro-astronomers, who have developed increasingly clever ways of visualizing the structure and function of the living brain. From the relatively crude days of CT scans to the truly impressive detail now being offered by functional MRI, this revolution in imaging technology is making it possible to study the course of AD in ways previously unimaginable.
There was a lot of talk of images at this meeting, most of it cordial. One session included a number of presentations addressing aspects of the use of various imaging modalities to diagnose and/or follow the course of AD. For example, Jonathan Chalk reported on a 12-month longitudinal study of AD progression using MRI. The rate of lateral ventricular atrophy was not as robust as hoped for. (Unfortunately, his data on this point didn’t show up on the slides, just the titles. Rather ironic for a talk on imaging!) Temporal lobe atrophy rate also showed overlap between AD and controls but the atrophy rates for the cerebrum in AD was about six times greater than in controls. Lateral ventricle rates were 7 times greater and temporal lobe atrophy was 5 times greater. Perhaps the most interesting aspect of this talk was the calculations of sample size needed to detect a treatment effect of 20 percent (85 patients to detect lateral ventricular atrophy, 189 for global atrophy and 288 for temporal lobe atrophy). Chalk also noted that a persistent technical limitation is the head movement of patients who are in the scanner.
Rachael Scahill followed with an intriguing display of images based on a method known as fluid-registered serial MRI. A comparison of images taken from the same patient over a period of several months will demonstrate areas of tissue loss and tissue gain. But it doesn’t actually reveal where the tissue is lost because it is based on comparisons of boundaries. To localize tissue loss, a different model is required in which the second scan is “warped” (are you listening Star Trek fans?) onto the first scan to provide a match that reveals measures of contraction or expansion. With this model it is clear that the atrophy is primarily in the temporal lobe (not surprisingly). When similar comparisons are made across several patients it is then possible to “normalize” the results using a template image in known standard space. What is seen with this kind of comparison? In mild cases, there is an expansion of the ventricles but contraction of posterior cingulate and temporal lobe regions (consistent with PET data). In later cases there appears to be a shift in atrophy from medial to lateral temporal lobe regions although it is not clear if this is an artifact.
Eric. Reiman reported on fluoro-DG-PET to track progression of cognitive changes in ApoE4 patients prior to any evidence of disease. They had earlier shown decreased glucose metabolism in brain regions that ultimately are affected by the disease in middle-aged patients but had recently extended the analysis to young (20-39-year old) subjects: 15 controls and 12 E3/E4 subjects who were matched for age, gender, education, MMSE and gender. No differences in neuropsychological performance were apparent. No differences in whole brain or pontine glucose metabolism were found, but parietal, temporal and posterior cingulate regions showed bilaterally reductions of around 10 percent in AD patients. These changes apparently precede the appearance of plaques and tangles with the exception of tangles in the entorhinal cortex. If follow-up indicates that these metabolic changes are predictive of disease risk, they may be used to monitor primary prevention therapies.
The most spirited discussion followed a talk by Daniel Silverman, who addressed the role of PET as a diagnostic tool. Based on the number of questions raised by this talk, I think it is fair to say that there is no consensus on the utility of PET for diagnostic purposes, but there was clearly a lot of interest in the extent to which imaging matches up with clinical and postmortem assessments. Other talks in this session supported the continuing role of imaging methods as both a diagnostic and experimental tool. One can only hope that the ability to monitor the progression of the disease will coincide with the development of therapies that interfere with its insidious course.
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