CONFERENCE COVERAGE SERIES
Society for Neuroscience Annual Meeting 2000
New Orleans, LA, U.S.A.
04 – 09 November 2000
Society for Neuroscience Annual Meeting: Stem Cells Drawn to Aβ
A central problem in Alzheimer's disease is to understand how Aβ affects the brain's biology, and how it contributes to neurodegeneration. A diverse array of mechanisms have been proposed, including direct toxicity, generation of oxygen radicals, and inflammation. In a poster (Abstract 181.11) presented today, Barbara Tate and colleagues at Boston Children's Hospital report a novel effect: Aβ may trigger signals that attract stem cells. Using adult rats, the researchers injected embyronic neural stem cells into one of the fluid-filled ventricles in the brain, and injected Aβ peptide into the contralateral ventricle. The transplanted stem cells migrated over to the Aβ-filled regions, whereas they did not migrate in control animals that had received a sham injection. Tate speculates that microglial activation, triggered by Aβ, is involved in signalling to the stem cells.—June Kinoshita
Reference:
"Migration of neural stem cells to Alzheimer's-like lesions in an animal model," by B.A. Tate, D. Wezanski, A. Marciniak and E.Y. Snyder.
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Society for Neuroscience Annual Meeting: Stem Cells Promising for Motor Neuron Disorders
Douglas Kerr and colleagues at Johns Hopkins (Abstract 209.13) reported success in using neural stem cells to restore function in an animal model of spinal motor atrophy (SMA). In SMA, the ventral horn motor neurons that innervate muscles slowly deteriorate. In humans, at one extreme the disease afflicts newborns and leads to death by two years of age. At the other extreme are patients who develop weakness later in childhood but live a normal lifespan. The disease has features in common with the much more prevalent amyotrophic lateral sclerosis (ALS, commonly known as Lou Gehrig's disease), in which neurons in both the spinal cord and brain degenerate.
The Hopkins team injected neural stem cells into the cerebrospinal fluid of mice and rats infected with the Sindbis virus, which selectively destroys ventral horn neurons. Nine of their 18 study animals recovered the ability to place the soles of one or both hind paws on the ground. Underlying this functional recovery, the researchers noted, was widespread stem cell migration into the spinal cord, with 5% to 7% of those cells differentiating into neurons, as shown by the expression of neuronal markers.
"We're working to explain how such an apparently small number of nerve cells can make such a relatively large improvement in function," said Kerr. "It could be that fewer nerve cells are needed for function than we suspect. The other explanation is that the stem cells themselves haven't restored the nerve cell-to-muscle units required for movement but that, instead, they protect or stimulate the few undamaged nerve cells that still remain."—Hakon Heimer
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Society for Neuroscience Annual Meeting: Does ApoE Contribute to Tangle Formation?
One of the earliest clues that apoE may contribute to AD pathology was the immunohistochemical demonstration by Namba and colleagues that ApoE was present in both plaques and tangles. ApoE did not really get serious consideration as a vital player, however, until the genetic association with ApoE4 was established by Roses and co-workers. Even so, the role of ApoE has been largely viewed as subordinate to that of amyloid, serving, at best, as a chaperone for the Aß peptide. Along the way there have been hints that ApoE may be more directly involved. For example, under some tissue culture conditions ApoE4 (and fragments of this protein) is toxic to neurons. [Disclaimer: This reporter contributed to the initial studies demonstrating ApoE toxicity and remains a firm believer in its relevance to AD pathology, i.e., I am biased. See the report on abstract 576.7 for more biased reporting.]
At the World Alzheimer Congress this past July, a group from the Gladstone Institute reported that C-terminal-truncated forms of ApoE (truncation that results in cytosolic accumulation of the protein) give rise to tangle-like structures when expressed in Neuro-2a cells. This week, the same investigators provided an update on this work (poster 202.8). In addition to documenting the filamentous nature of the tangle-like structures using electron microscopy, they found that the tangles were immunopositive for phosphorylated tau (p-tau) and the heavy neurofilament protein. Furthermore, ApoE co-precipitates with p-tau from the transfected cells. Intriguingly, treatment of the cells with Aß leads to greater proteolysis of ApoE. They further demonstrated that truncated ApoE fragments are present in human brain homogenates (in agreement with our own earlier studies) with the important additional finding that there are differences in the types of fragments present in the insoluble pellet and the supernatant. In particular, the ApoE fragments are in much greater abundance in the pellet from AD homogenates as compared to control homogenates, suggesting their precipitation with other components. They also demonstrated higher molecular weight complexes (approx. 220 kDa) that form from ApoE and p-tau. In answer to a question from the audience, Dr. Huang noted that these transfections inevitably lead to cell death within two to three days, suggesting that these constructs are ultimately toxic.
What does it all mean? Well, for one thing, the finding that intracellular truncated ApoE may contribute to cytoskeletal abnormalities resembling tangles emphasizes the importance of the original observation of Namba et al. that AD tangles stain for ApoE. In addition, if the effects of truncated ApoE are connected in some way to the previously reported toxic effects of ApoE, this could provide a hint as to the role of this protein in AD neuropathology, in addition to its putative role in contributing to amyloid deposition. (More on this idea is found in the report on abstract 576.7.)—Keith Crutcher. Abstract #202.8.
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Society for Neuroscience Annual Meeting: A Glimpse into the Future?
The award for most aesthetically pleasing presentation almost certainly could go to Dr. Paul Thompson, who reviewed recent advances being made by a UCLA team in developing AD-specific brain atlases for assessing alterations in the brain over time (Abstract 110.4). The presentation was a whirlwind tour of the techniques used to develop these novel atlases and some results that point to great promise in their utility for examining dynamic changes in AD brains. As an old-time neuroanatomist, I had to struggle to keep up as phrases like "3-D vector displacement", "tensor mapping" and "warping field" flew by. But this Star Trek terminology did not obscure the stunning visual displays of brain anatomy (which I could appreciate) and the major point that focal changes in discrete brain regions can be visualized as the disease progresses.
My dumbed-down version of this elegant presentation follows: If one takes a 3-D spatial average of a group of AD brains (easier said than done, by the way), you can then use the average model for comparisons with another average model derived from either control brains or the same AD brains averaged from scans taken at a later point in time (perhaps after being on a certain treatment). This allows one to determine whether changes, e.g., atrophy, are likely to be due to random variation as opposed to the disease itself. The resulting 4-D atlas (three dimensions in space over time) can be used to examine changes in local regions such as the hippocampal formation, where initial data suggest that some focal changes might be obscured by studying the structure as a whole.
In other words, with these methods, it should be possible to monitor the rate and extent of brain changes and correlate those changes with cognitive performance and, ultimately (once postmortem data are available), histopathology. In a brief interview with him after his presentation, Dr. Thompson told me that the methods were initially developed to study changes in brain growth during development. Applying these methods to AD changes came from an interest (and presumably funding) from SmithKline Beecham, who approached Dr. Thompson with the idea of developing the AD brain atlas with the ultimate goal of being able to determine whether specific treatments are effective. The first step was to determine where, and at what rate, degenerative changes occur. In addition to being visually stunning, the results point to the possibility of establishing a means of ultimately detecting early changes that might be a harbinger of more serious pathology to come. Such early warning signals could make a critical difference in warding off the long-term pathology when effective treatments hit the market. Heady stuff? Indeed. But my bet is that this technology is where the future of AD clinical research is headed. And if this is the future, I say, "Beam me up, Scotty!"—Keith Crutcher
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Society for Neuroscience Annual Meeting: Triumph of the NERD
At least I hope they will come. Brian Cummings presented an overview of a web-based database for Alzheimer’s cases (known as the Neuropathological Examination Research Database or NERD) that could serve as a model for other AD centers (Abstract 679.7). The database has been under development for some time and is now available online at www.alz.uci.edu/nerdplus. A simple registration process is required to use the service. I was able to get into the database in less than five minutes. Dr. Cummings highlighted the major features of the site, which provides detailed (but anonymous) information on patients' clinical history as well as key data points relating to vital statistics and neuropathological features. The site is designed to provide access to summary data with easy navigation to more specific information as needed. It is also possible to carry out advanced searches which permit selection of cases based on any of several criteria. When I tried it out, I found it to be easy to navigate and well-organized. A feature I found especially useful is the extensive database of neuropathological images. As someone who has obtained tissue from the UCI brain bank, I can attest to the high quality of service and support provided by this group. The development of this online database is further evidence of the commitment of this center to broader service to the AD research community. The plan is to add data provided by investigators who carry out studies with tissue provided by the center. This is an important development that will no doubt accelerate the pace of research by providing more access and exchange of data. When an aging neuroanatomist like myself can figure out how to make use of a system like this, need I say more?—Keith Crutcher
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Society for Neuroscience Annual Meeting: TrkA Receptors Down-regulated in MCI
It has previously been reported that the nerve growth factor (NGF) receptor trkA is depleted within the nucleus basalis, which is selectively damaged in early Alzheimer's disease. In a study presented this past Tuesday in a poster (Abstract 575.11), Yaping Chu and colleagues at Rush Alzheimer's Disease Center push back the time line for trkA loss to an earlier stage of disease progression. The researchers analyzed nucleus basalis tissue from 26 participants in the Religious Orders Study. All of the individuals had undergone clinical evaluation within 12 months of death. Roughly half of the individuals were categorized as having no cognitive impairment, and the rest had mild cognitive impairment (MCI) or mild Alzheimer's. The MCI and Alzheimer's individuals had a significant loss (15.8 percent and 20.4 percent, respectively) of trkA gene expression in the nucleus basalis, as compared with the control group. "These preliminary results suggest that a down-regulation of trkA mRNA occurs in early cognitive decline," the authors write.—June Kinoshita
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Soc for Neurosci Annual Meeting: Explaining Finicky Toxicity of Aβ
It's a poorly kept secret that Aβ peptides are highly inconsistent in their neurotoxic properties. One batch of synthetic peptide will kill neurons handily, while another will be benign. Sarah Wright and her colleagues at Elan Pharmaceuticals think they may have found an explanation (Abstract 475.12). Using atomic force microscopy and transmission electron microscopy, they examined the structure of Aβ1-40 peptides from different preparations and found that neurotoxicity correlates directly with the composition of aggregate states. All neurotoxic preparations contained a mixture of both fibrils and unaggregated Aβ. Interestingly, adding a small amount (75%) in primary human and rat cortical neuron cultures. Wright suggests the fibrillar form seeds an ongoing aggregation process, which yields a supply of "protofibrillar" or oligomeric Aβ that is the actual toxic entity, as previously reported by Dean Hartley and William Klein. If others can confirm that mixed preparations are the key to toxicity, one hopes that the debate over Aβ's role can advance to the next level, of determining the toxic mechanism at work and its relevance to Alzheimer's.—June Kinoshita
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Society for Neuroscience Annual Meeting: The Ghost of D’Arcy Thompson
What do ßamyloid, buckyballs, and dark matter have in common? They were all mentioned in an intriguing presentation by Dr. Westlind-Danielsson (AstraZeneca, Abstract 299.2) on the formation of spheroidal "supramolecular structures" by amyloid 1-40 under "near-physiological conditions (50mM NaHPO.NaHPO, pH7.4, 100mM NaCl at 30oC)". These "ßamy-balls" (in honor of the buckyballs formed by buckminsterfullerene) range in diameter from 20-200 µm (similar in size to AD plaques) and consist of 6-10 nm diameter fibrils. They are stable for up to three weeks and, if left to dry, form an intriguing network-like structure (reminiscent of the large scale structure of the universe based on the distribution of dark matter and the lattice of buckyballs). They do not form from pure Aß1-42, although mixtures of the two amyloid peptides do give rise to the structures.
Perhaps what is most remarkable about amy-balls is that they form in a completely cell-free environment. In other words, this molecular behavior arises from the biochemical features of this peptide, which has been known for many years to spontaneously form fibrils. Other aggregating peptides do not show the same behavior under the same conditions. A century ago, D’Arcy Thompson was a proponent of the importance of understanding physical constraints on biological systems. His opus, "On Growth and Form", emphasized the molding influence of physico-chemical forces on the shape and function of cells and larger organisms. The amy-balls are reminiscent of such phenomena and may provide a means of modeling some of the physical properties of the spheroidal pathological features found in a variety of neurodegenerative diseases, including Alzheimer’s plaques. Certainly, the fact that such structures emerge spontaneously in a test tube point to the possibility that some of the structure of plaques could be due to similar physicochemical forces. What it may reveal about the large scale structure of dark matter in the universe will no doubt require further investigation. (I’d love to see the grant proposal for that!)—Keith Crutcher
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Society for Neuroscience Annual Meeting: ApoE Critical for Both Plaque and Tangle Formation?
Being both an active scientist and a part-time reporter leads to some interesting situations. Most of the time, my scientific background could be considered an advantage when evaluating reports because I should have a better understanding of the field as compared to those not working in it. On the other hand, my scientific views necessarily lead to a bias in both the work that I do and the news that I report. The most direct conflict arises when evaluating the work done in my own laboratory. Obviously, I think the work is important and relevant, otherwise I wouldn’t be doing it. Whether it is "newsworthy" is harder to assess. So before taking advantage of my position as a reporter to highlight work from my lab, I waited to see what kind of response there was to a poster (abstract 576.7) we presented at this meeting. There was a continuous stream of interested individuals (folks who actually stopped to read the poster and ask questions), most of whom expressed the opinion that they thought the work was both interesting and potentially important. So with that as my polling sample, I am providing a brief summary of the salient results.
As noted in my report on the Huang talk (abstract 202.8), ApoE’s role in AD has been difficult to pin down. We had reported some years ago that ApoE peptides, the N-terminal fragment of ApoE (truncated ApoE) and full-length ApoE exhibit neurotoxic effects with the E4 isoform being more toxic. There has also been a fair amount of evidence that ApoE contributes to amyloid deposition, perhaps mediated by binding to amyloid through the C-terminal portion of ApoE. Whether ApoE fragments exist in the human brain has been a controversial claim (I can say this with some authority). The results presented in our poster suggest that truncated ApoE is present in human brain and that there is an increase in the proportion of this fragment in AD brain as compared to control tissue (the highest ratio being found in ApoE4/4 cases). Furthermore, immunohistochemistry carried out with different ApoE antibodies suggests that apoE staining of plaques is obtained with almost any anti-ApoE antibody, but is especially prominent with a monoclonal antibody raised against a C-terminal epitope. The same antibody, however, gives little staining of the neurofibrillary pathology. Antibodies directed against the N-terminal part of ApoE, on the other hand, reveal the neurofibrillary pathology.
The bottom line hypothesis is that ApoE contributes to both plaque and tangle formation via C-terminal and N-terminal fragments, respectively, that are products of ApoE proteolysis. The pathway to plaque formation presumably involves amyloid deposition through interactions with the C-terminal fragment. How tangles might form is still a matter of speculation, but there is increasing evidence that the receptor-binding domain of ApoE is involved in signaling and, perhaps, neurotoxic effects. Once ApoE gets internalized, it may be able to interact with cytoskeletal components to affect tangle formation as suggested by the work of Huang et al. (reported elsewhere). So there it is. A working hypothesis that may have some heuristic value for understanding the role of ApoE in AD. Or maybe not. The fun of science is growing hypotheses and seeing whether they thrive. The lifespan of this particular idea remains to be determined.—Keith Crutcher
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Society for Neuroscience Annual Meeting: LRP: Guilt by Association
One of the most daunting tasks facing attendees of this gigantic neuroscience data exchange (dare I say "flea market"?) is identifying signals in the noise (speaking both scientifically and literally). One approach is to sit through slide sessions and hope that the organizers will have done your work for you, providing a series of talks that will be both illuminating and informative. And sometimes this works. But there seems little doubt that most scientific exchange occurs at the poster sessions, an endurance test for veterans and novices alike. But here again, it is still difficult to know whether or not a particular observation represents a fluke or an emerging theme. So one approach to signal detection is to see whether or not the same message crops up in different places. On this count, there is an interesting tale in the making and the central player is a rather enigmatic protein tongue-twistingly named the low-density lipoprotein receptor-related protein (LRP, for short). What exactly this receptor is doing is hard to say with certainty. But it keeps cropping up in interesting places and seems to be hanging out with all the big AD players, e.g., Aß, APP, A2M, and ApoE.
Several posters from different laboratories reported on various aspects of LRP activity. For example, a group from San Diego (Abstract 858.11) found that LRP may be critical for clearing Aß in cultured cells. This apparently occurs by way of a complex formed between Aß and A2M. Another group from Boston (Abstract 858.13) has previously shown that LRP can bind and internalize the KPI form of APP, perhaps leading to Aß production as a result. They provided further evidence at this meeting that LRP can bind and internalize both APP and A2M using radiolabeled ligands. Yet another group from California (Abstract 858.14), which previously found that TGFß2 can deliver Aß to hippocampal neurons (TGFß1 apparently delivers Aß to microglia), found that the uptake into neurons (but into microglia) was blocked by RAP, a protein that inhibits binding of LRP ligands. The evidence is a bit more indirect, because RAP can bind to other members of the LDL receptor family, but it is consistent with the possibility that this interaction is also mediated by LRP. Other evidence suggests that this receptor may be playing roles in intracellular signaling. For example, calcium increases in cells exposed to ApoE or peptides derived from the receptor binding domain of ApoE can be blocked by RAP (Abstract 665.7) and A2M also causes calcium signaling through a mechanism that implicates both LRP and the NMDA receptor (Abstract 859.13). All in all, the mounting evidence points to LRP as doing something (maybe several things) but with so many potential partners and cellular effects, it could be a while before anyone is able to decipher the precise contribution it may make to AD pathology. The number of talented laboratories joining the search, however, provides hope that the answers will be coming soon.—Keith Crutcher
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Society for Neuroscience Annual Meeting: Immunization of Mice and Men
What is the latest on the immunization of mice and men with Aβ? Will we be celebrating victory over Alzheimer’s disease in a few years (and looking for new jobs), or has the story been overrated? One would predict to see a number of posters and talks at this year’s meeting on Alzheimer’s immunization paradigms, and we weren’t disappointed. Which form of immunization works best, passive or active? Are the results similar in APP-Swedish mice versus APP-PS1 doubly transgenic mice? Are there clear behavioral impairments in AD-transgenic mice and can these deficits be reversed by immunization?
Two recent reports have raised hope that immunization with Aβ peptides may block deposition of β-amyloid or even promote removal of existing plaques. Schenk and colleagues (Nature 1999) were the first to show that active immunization of PDAPP transgenic mice (which overexpress a mutant form of APP) with Aβ peptide could prevent or reverse the accumulation of β-amyloid plaques. If immunization was given prior to plaque formation (six weeks), virtually no plaques were detected in adult mice. Later immunization greatly reduced the amount of plaque material if administered after plaque formation was well under way (11 months). Weiner and Lamere from Selkoe’s group have reported similar results in PDAPP transgenic mice when the antigen is administered via a nasal route (Annals of Neurology 2000).
With this background, some key questions are whether these results would be replicated, and replicated in other transgenic models, whether passive immunization can yield similar results, whether there is evidence for IgG mediated clearance of amyloid, and whether there are behavioral consequences to immunization therapy.
The short summary is that yes, immunization with Aβ leading to a reduction in plaques has been replicated now by other groups in both PDAPP mice and APP-PS1 doubly transgenic mice. Both active (using Aβ peptide as antigen) and passive (injecting anti-Aβ IgG produced in another animal) methods are effective. Fc receptor anti-Aβ IgG mediated clearance of Aβ via microglia has been demonstrated. And clear behavioral consequences have been demonstrated. Since it would be too time consuming to report on each of these aspects, the remainder of this report focuses on two behavioral studies demonstrating that immunization with Aβ attenuates cognitive deficits in Tg AD-like mice.
Yu and colleges at the University of Toronto presented an excellent poster (Abstract 181.18) on a long-term behavioral study of APP-CRND8 transgenic mice (C3H/B6) overexpressing (by fivefold) the Swedish mutant form of APP. At 11 weeks, these mice show increases in levels of soluble Aβ via SDS gels and cortical Aβ positive plaques. They first demonstrated that injection of complete Freund's adjuvant or incomplete adjuvant had no effect on learning acquisition or reversal learning in control mice. After examining a variety of tasks, they determined that APP-CRND8 Tg mice exhibited an age-related cognitive impairment in acquisition and reversal of spatial learning using a reference memory version of the Morris water maze. They replicated the immunization protocol of Schenk (1999) in six-week-old mice (e.g., injections at 6, 8, 12, 16 and 20 weeks) using Aβ42 and islet associated polypeptide (IAPP) as an additional control. At 11 weeks, all mice received nonspatial pre-training in the water maze.
At 11 weeks, there was already a difference in the performance of Aβ immunized Tg mice when compared to IAPP immunized mice, although Aβ immunized mice did not perform as well as non-Tg controls. The Aβ immunized mice continued to improve on the task at 15, 19 and 23 weeks, while the IAPP immunized mice improved somewhat at 15 weeks, began to get worse at 19 weeks and much worse at 23 weeks. At 23 weeks, IAPP-mice could learn, but required more sessions. And at no time did the IAPP mice perform as well as the Aβ immunized mice. By the end of testing, the Aβ immunized mice were performing almost as well as the non-Tg mice. Following sacrifice at 25 weeks, Aβ load was measured in hippocampus and cortex, and both regions had significantly less Aβ deposition compared to IAPP-mice. Because there were only six Aβ immunized mice, a correlation between Aβ load and cognitive impairment was difficult to establish; however, for four mice, there was a “perfect correlation between Aβ load and performance … with one borderline animal and one outlier” (data not shown).
In a parallel study (also not shown), in collaboration with Paul Matthews at the Nathan Kline Institute in NY, similar mice were immunized and Aβ measured. The first changes to be detected were a decrease in plaque loads, which were later followed by decreases in Aβ as measured by ELISA. This poster left me convinced that immunization with Aβ in Tg mice can reduce cognitive impairment in an animal model. In particular, the control experiments conducted were extensive and convincing. One take-home message was that the selection of the behavioral test is critical in detecting cognitive impairment in the Tg mice. It remains to be seen whether the immune system in man can be primed sufficiently without going into overload, or whether there will be autoimmune problems. (However, passive immunization studies reported at this meeting suggest this can be avoided.)
Moving on to a doubly transgenic model (APP/PS1 mutant mice) from David Morgan and colleagues at the University of South Florida, there were a series of talks that covered the gamut, from the effects of calorierestriction (181.15) to blueberries (664.3), to when maximal titer is achieved (397.5) to behavioral effects of immunization (398.6). This is one well-studied group of mice. My notes indicate that David Morgan presented Abstract 397.5, not Gordon, but I admit it's all a blur now (and this has no correlation to number of Hurricanes consumed, n=1). My notes do indicate that following 3 to 4 vaccinations, the titer of Aβ IgG has reached maximum in these APP/PS1 mice (following a similar vaccination procedure to Schenk 1999). In the short-term study (three injections), there were no significant decreases in Aβ measures (ELISA and Aβ load), however, in the long term study (eight monthly injections), there was a 20% reduction in Aβ. As a percentage of control, the observed reductions are greater in singly mutant APP mice compared to APP/PS1 doubly mutant mice. However, in absolute terms, the reduction in area was greater in APP/PS1 mice compared to APP-only mice. David suggested that there was perhaps an upper limit in the amount of Aβ that could be removed. When asked if there was a relationship between microglia activation and Aβ load, David indicated no, but cautioned that they had only looked in short-term mice where there was less Aβ.
A separate talk on the behavioral performance in these same mice prior to and following vaccination was presented by Arendash (Abstract 397.6). As mentioned above, and at their poster (275.5), task selection is critical if one is to detect cognitive deficits in these mice. For example, Tg positive mice are not impaired in the Y-maze or the standard Morris water maze tests (circular platform performance). However, they are impaired in a radial arm water maze acquisition (RAWM). And there is also an age-related deficit in short-term (working) memory. And then Arendash talked about the effects of vaccination on RAWM task in these APP/PS1 doubly transgenic mice. Non-Tg mice exhibit no age effect on this task, while Tg mice are indistinguishable from controls until 15.5 months when their performance declines (and when Aβ levels are high). There is also a correlation between performance on the RAWM and Aβ load. In the current study being reported at the Neuroscience meeting, Tg and non-Tg mice were trained and tested between six and seven months on the RAWM and then immunized with Aβ peptide (between 7.5 and 11.5 months the animals received one vaccination/month). Retesting at 11.5 months (e.g., after four months of immunization) showed no differences between Tg-, Tg+ and Tg++Aβ mice. From 11.5 months to 15.5 months, additional vaccinations followed. At 15.5 months (following eight injections), the Tg++Aβ mice were tested again on the RAWM and while it still took them longer to reach the performance of controls, they were indistinguishable from Tg- control mice on the last two trials of block 3 of testing. This study is particularly nice because all animals started out the same in performance at 11.5 months and differences were only seen over time.
While no one reported on human studies at this year’s meeting, you can be sure trials are under way. Hey, does this mean that those of us weighing out and inhaling Aβ dust all these years can expect some measure of protection?—Brian Cummings
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Soc for Neurosci Ann Mtg: β-Amyloid Triggers CD40 Expression in Microglia
CD40 is a member of the TNF receptor superfamily, which includes TNFR-1, TNFR-2, Fas, CD27, RANK, DR4 (TRAIL-R1), DR5 (TRAIL-R2), and DR6, as well as assorted decoy receptors (e.g., DcR-1/TRAIL-3). The TNF receptor superfamily is characterized by an extracellular domain containing two to six repeats of a cysteine rich motif. Many of these receptors are expressed on neurons in animal models of injury, and recent reports have demonstrated their expression in the AD brain.
It is clear that microglial cells play a key role in modulation and mediation of immune responses in the brain. Michael Mullan’s group has previously demonstrated that interferon-g (IFN-g) increases CD40 expression in cultured brain microglia, and that microglial activation by CD40 ligand (CD40L) in the presence of IFN-g results in increased TNFa production and TNFa?mediated cortical neuron toxicity in vitro. Given recent evidence for the role of microglial activation in Aβ clearance in active and passive immunization studies in animal models of AD, and pending studies on the clinical applicability of this approach, the mechanisms and secondary consequences of microglial activation by Aβ are of current interest.
In this study (Abstract 299.13), the authors demonstrate increased expression of CD40 in cultured brain microglia treated with very low doses of β-amyloid (Aβ) 1-40 or 1-42 peptides (500nm). In parallel with previous observations, microglial activation by CD40L in the presence of Aβ resulted in increased TNFa production and neurotoxicity in neuronal co-cultures. Moreover, CD40 expression was also increased on microglia in a transgenic mouse model of AD (Tg APPsw). Crosses of Tg APPsw mice with CD40L-deficient mice exhibited reduced microglial activation in tissue sections, and reduced TNFa release in microglial cultures derived from these animals. Interestingly, tau hyperphosphorylation, e.g., as detected with AT-8, was decreased in 8 month old Tg APPsw/CD40L-deficient animals. These data suggest that Aβ-stimulated microglial activation and TNFa production is dependent on CD40L, and that CD40-CD40L interactions may play a role in AD pathogenesis.
Further References:
Mullan M, Town T, Paris D, Crawford F, Tan J. Department of Psychiatry. The Roskamp Institute, Tampa, FL, USA. The CD40 pathway mediates β-amyloid-induced microglial activation. Society for Neuroscience Abstract 299.13.
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Society for Neurosci Ann Mtg: Passive Aβ Immunization Works in Mice
A current working hypothesis in the field of AD research is that preventing the accumulation of Aß peptides will slow or prevent cognitive decline. Two main strategies for accomplishing this goal have been pursued in recent years. The first strategy is to derive pharmaceuticals that will block the activity of the γ-secretase, which drives the generation of toxic amyloidogenic fragments from APP. This strategy is similar to that applied in the clinical use of statins, which inhibit HMG-CoA reductase, thus lowering cholesterol by preventing deposition and promoting clearance, and decreasing the incidence of disease in vulnerable populations. The second strategy is to directly target the clearance of Aß from the neuropil. Recent work has demonstrated that active immunization of mutant human APP-overexpressing transgenic (PDAPP) mice with Aß peptides stimulates the immune system to recognize these peptides and clear them from the neuropil. However, serious concerns regarding the consequences of such an approach in humans have been raised. A principal worry is that active immunization against an endogenous protein in humans could result in a detrimental autoimmune response or other complications in a percentage of the clinical AD population.
Bard et al. provide both a test of the validity of antibody-driven Aß clearance using passive immunization, and an alternative to vaccination as a therapeutic approach to immune-mediated AD therapy (Abstract 397.1). 8-10 month old PDAPP mice received either intraperitoneal anti-Aß antibodies or PBS every week for six months. Normally, PDAPP mice exhibit dramatic Aß accumulation in neuropil plaques by 12-18 months of age; this Aß plaque burden was reduced by over 90% in mice treated with anti-Aß antibodies. Surprisingly, peripherally administered anti-Aß antibodies were found to decorate plaques in treated mice, as demonstrated by immunocytochemistry. Vascular permeability and the concentration of endogenous immunoglobulins were unaltered in the brains of treated mice, suggesting that the blood-brain barrier was intact.
The hypothesized mechanism of immunization- and antibody-stimulated clearance of Aß is via phagocytic brain microglia. The authors tested microglia-mediated Aß clearance in an ex vivo assay, which combined fresh frozen PDAPP mouse cryostat sections with primary mouse microglial cultures. The results of these studies suggest that cultured microglia can effectively phagocytize Aß in tissue sections treated with anti-Aß antibodies that bind plaques in situ, but not in sections treated with control antibodies or anti-Aß antibodies that do not bind plaques in situ. Critically, the authors also show evidence supporting the degradation of phagocytized Aß peptides in this model. In principal, antibody-stimulated Aß clearance by microglial phagocytosis should be dependent on the constant (Fc) region of anti-Aß IgG antibodies. Thus, to further test the hypothesis that Aß clearance in this model is antibody-dependent, the authors investigated the effect of treatment with F(ab’)2 fragments, which contain only the variable (antigen binding) regions of the IgG molecule, in lieu of whole IgG. As predicted, while F(ab’)2 fragments still decorated PDAPP plaques, indicating interaction with accumulated Aß peptides, they were ineffective at promoting Aß clearance by microglial phagocytosis in the ex vivo assay. Hence, these findings point to Fc-receptor-mediated microglial activation as the mechanism of Aß removal.
This study provides a tantalizing view of the potential for therapeutically targeting the immune system to treat AD. Moreover, the ability of therapeutic levels of monoclonal antibodies to enter the central nervous system could have implications for other neurodegenerative diseases that are associated with toxic or abnormal proteins, including Huntington’s disease and the spongiform encephalopathies. Additional studies investigating the clinical applicability of these findings to AD are currently under way, and could provide one of the first treatments aimed at the neuropathological mechanisms underlying dysfunction and degeneration in AD. However, a significant component of the neurodegenerative damage caused by Aß peptides could result from intracellular accumulation, and may be unrelated to plaque deposition in the neuropil . Additionally, APP overexpressing transgenic models do not exhibit gross neuronal loss or the full inflammatory response associated with AD. Thus, the efficacy of such a treatment for stabilizing neurodegenerative changes such as synapse and neuron loss, and the capacity for this strategy to meaningfully stabilizing or improving cognitive function, remain unknown.—Aileen Anderson
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Society for Neuroscience Annual Meeting: Plaques Vanish Before Our Very Eyes
Last year, Brad Hyman’s group reported on their ability to image amyloid plaques in the brains of live PDAPP Tg mice. Plaques could be detected as deep as 200 microns and the same plaques could be imaged over the course of weeks using a multiphoton laser scanning microscope (see Abstract 120.11 from 1999). With all the recent fervor over vaccination treatments for Alzheimer’s disease, it was only natural for them to turn their attention to the effects of immunization on "living" plaques. While there is little doubt that active immunization with β-amyloid in mice Tg for APP can inhibit plaque formation and likely promote the clearance or partial clearance of preexisting amyloid deposits as well, over what time frame do these events occur, and can we watch the process happen? Bacskai, Hyman and colleagues presented data on the reliability and reproducibility of imaging plaques in live PDAPP mice and the effects of passive administration of anti-beta-amyloid antibodies (Abstract 397.2). The process uses high resolution near infrared imaging to yield images with a 1 micron voxel resolution as deep as 200 microns below the cortical surface. Mice are surgically prepped by removing a small piece of the skull over the region of interest to expose the cortical surface.
Using fluorescein injected i.v. to allow imaging of blood vessels, and thioflavine to image β-pleated amyloid deposits, they were able to find the same volume of tissue for more than a month and observe stable plaques. In a set of animals, 65 thioflavine-positive plaques were detected and antibodies against β-amyloid (10D5) were applied to the surface of the brain. Within three days, 70 percent of these plaques were cleared. A control antibody failed to clear any plaques.
In a separate experiment, anti-10D5 tagged with FITC was applied to both detect diffuse plaques and induce clearance. Again, over three days the diffuse plaques were cleared. There was concern that the "diffuse" experiment is not as clean as the fibrillar experiments because the same IgG used to detect the plaques was used to induce clearance and redetect the plaques.
It is possible (but not likely), that the detection step would be hindered by already present IgG. However, the thioflavine-based experiments do not have this issue and one would think those fibrillar plaques would be harder to clear than diffuse plaques. In addition, animals were sacrificed and sections taken of the fields imaged. In a side view showing the depth of cortex, one could clearly see a concave zone of cortex below the imaging window that was devoid of plaques. Adjacent sections showed a cluster of tomato-lectin positive microglia within the zone of cleared plaques. Thus, both diffuse and compact plaques can be cleared via passive immunotherapy.
Great news for those of use who worry about an autoimmune response in man. Of course, there is still the issue of activating the immune system and cytokine responses in man versus mice, where APP is under a different promoter. In man, an enhanced inflammatory response may increase the production of APP.—Brian J Cummings
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Society for Neuroscience Annual Meeting: The Calcium-Presenilin Connection
Several presentations focused on the role of presenilins in calcium signaling pathways. Leissring and LaFerla (Abstract 474.7) reported that cells from mutant PS1 knockin mice are deficient in capacitative calcium entry (i.e., the influx of calcium triggered by depletion of intracellular calcium stores), a finding they recently reported in J Cell Biol;149: 793-798. Intriguingly, Kim, Tanzi, and colleagues (abstract 474.9) found that inhibitors of capacitative calcium entry lead to increased β-amyloid production, suggesting that this signaling pathway may regulate presenilin-mediated γ-secretase activity. In support of this regulatory link, Leissring et al. found that a tight correlation exists between the relative amount of β-secretase activity in PS1 and PS2 knockout cells and their sensitivity to agonists that stimulate release of intracellular calcium. LaFerla’s group provided evidence that presenilin mutations alter intracellular calcium levels, leading to increased calcium in the endoplasmic reticulum. This finding was nicely complemented in a nearby poster by Yang and Cook (Abstract 474.8) showing that intracellular calcium stores are, conversely, decreased in neurons from PS1 knockout animals. Finally, Sisodia (Abstract 298.5) showed evidence that a region of the presenilin molecule is homologous to potassium channels, raising tantalizing new questions about the role of presenilins in ion homeostasis. Clearly, interest in the role of presenilins in ion signaling is gaining momentum, and several interesting stories are bound to emerge in this area in the near future.—Brian J Cummings
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Society for Neuroscience Annual Meeting: Synuclein and Parkin Roundup
Reported by Benjamin Wolozin, Natalie Golts and Peter Choi, Loyola University Medical Center
The meeting in New Orleans demonstrated that the biology of α-synuclein and parkin are progressing at a rapid pace. Aggregation of α-synuclein is thought to play a pivotal role in the pathophysiology of Lewy body disease. Several studies presented advances in our understanding of the biology of α-synuclein aggregation. Ueda and colleagues (13.1) showed that α-synuclein binds tubulin and that tubulin fibrils act as nidus points that stimulate aggregation of α-synuclein. This is particularly interesting because dystrophic neuritis in Lewy body diseases are known to accumulate α-synuclein, and the ability of tubulin to serve as a nidus for α-synuclein aggregation provides a mechanistic underpinning for this phenomenon.
Golts, Wolozin and colleagues (13.5) looked at binding of metals to α-synuclein. They showed that iron promotes α-synuclein aggregation and magnesium inhibits aggregation. As with the work on tubulin, this work might shed light on mechanisms of α-synuclein aggregation in Lewy body diseases because brains of patients with Parkinson’s disease have increased iron and decreased magnesium, both of which would tend to promote α-synuclein aggregation.
Murray, Trojanowski, Lee and colleagues (84.10) also looked at the biochemistry of α-synuclein aggregation. They suggest that amino acids 71-82 are critical for α-synuclein aggregation. They also examined pharmacological agents that might inhibit aggregation of α-synuclein. Congo-red and thioflavine are known to bind to β-pleated sheet structures and inhibit aggregation of Aβ. They observed that congo-red, thioflavine and analogues of these molecules also inhibit α-synuclein aggregation. Lee, Lansbury and colleagues (1 3.4) looked at the consequences of aggregate formation. They observed that α-synuclein protofibrils bind to phospholipid vesicles better than does monomeric α-synuclein. Interestingly, they suggest that the protofibrils form a channel that is permeable to calcium, which suggests a novel mechanism of cell death in Lewy body diseases.
A number of groups investigated the subcellular distribution of α-synuclein aggregates. George, Clayton and colleagues (84.11) showed that aggregated α-synuclein associates with the membrane fraction. In contrast, Sharon, Goldberg and Selkoe (84.6) fractionated brain tissue from transgenic mice and lysates from dopaminergic neurons, and they suggest that α-synuclein localizes to the microsomal fraction. Leng, Chase and Bennett (478.18) looked at the distribution of α-synuclein in SY5Y cells and observed that carbachol induces a reversible translocation of α-synuclein from the plasma membrane to cytosolic vesicles. Perez and colleagues (84.15) looked more specifically at the function of α-synuclein and showed that α-synuclein binds to tyrosine hydroxylase and inhibits it activity.
The models of α-synuclein-induced neurodegeneration and Lewy body degeneration are also improving. In a pre-meeting symposium, Greenamyre and colleagues showed that mice treated chronically with the mitochondrial complex I inhibitor, rotenone, develop a syndrome strongly resembling Parkinson’s disease, including production of inclusions resembling Lewy bodies and degeneration of neurons in the substantia nigra (1). M. Lee and colleagues (13.3), Kahle and colleagues (13.6) and Goldberg, Shen and colleagues (84.7) presented a transgenic mouse that develops diffuse pathology in multiple brain areas (including the brain stem, cerebellum and cortex), and which develops pronounced motor deficits. These rodent models will provide a strong basis for future experiments aimed at inhibiting Lewy body pathology.
A number of groups also presented advances in our understanding of parkin. Schlossmacher, Kosik, Selkoe and colleagues (13.7) characterized the distribution of parkin in the brain. They observed that N-terminal anti-parkin antibodies stained virtually all Lewy bodies, suggesting that parkin is a ubiquitous component of Lewy bodies. Tsai, Fishman and Oyler (13.9) and Rankin and colleagues (13.10) both presented evidence from in vitro studies confirming that parkin functions as a ubiquitin ligase. Oyler and colleagues (13.8) examine a specific apoptotic protein that itself appears to be a ubiquitin ligase and suggested that impaired ubiquitin metabolism might stimulate neurodegeneration by altering the levels of proteins that regulate apoptosis. Choi, Wolozin and colleagues (13.11) and Zhang, Dawson and colleagues (476.3) both looked at specific proteins that bind parkin in cells. Both groups identified septins in the hCDCrel family (hCDCrel-1 and 2a) as parkin binding proteins. Zhang, Dawson and colleagues showed that parkin regulates the degradation of hCDCrel-1. This latter work was recently published. Choi, Wolozin and colleagues also identified filamin-1 as a protein that binds parkin. Identification of specific proteins whose catabolism is regulated by parkin will enable more detailed understanding of its function.
13.1 Ueda et al. Identification of α-tubulin as a binding partner of NACP (α-synuclein) and its involvement in Lewy body formation in Parkinson’s disease and in multiple systems atrophy.
13.3 Lee MK et al. Neuronal and behavioral pathology in a transgenic mouse expressing α-synuclein.
13.4 Lee SJ et al., Vesicle binding and permeabilization by nonfibrillar β-sheet containing oligomers of α-synuclein: a trigger for cell death in Parkinson’s disease.
13.5 Ostrerova NV et al., The A53T α-synuclein mutation increases iron-dependent aggregation and toxicity.
13.6 Kahle PJ et al. Subcellular localization of wild-type and Parkinson’s disease associated mutant α-synuclein in human and transgenic mouse brain.
13.7 Schlossmacher MG et al. Characterization of parkin protein in brain and transfected cells.
13.8 Oyler GA et al. XIAP as an E3 ubiquitin ligase in neurodegeneration.
13.9 Tsai Y et al. Parkin functions as an E3 ubiquitin ligase and regulator of the proteosome.
13.10 Rankin CA et al. Parkin has E3 ubiquitin ligase activity.
13.11 Choi P et al. Parkin associates with the actin-binding protein filamin.
84.6 Sharon R et al. A subcellular fractionation study of wt and A53T mutant α-synuclein expressed in transgenic mouse brain and MES 23.5 dopaminergic neuronal cells.
84.7 Goldberg MS et al. Studies of human α-synuclein in transgenic mice.
84.10 Murray IVJ et al. Inhibition of α-synuclein aggregation in vitro.
84.11 George JM et al. α-synuclein self-association inhibits binding to phospholipid membranes.
84.15 Perez RG et al. α-synuclein may be a chaperone for tyrosine hydroxylase.
476.3 Zhang Y et al. Functional characterization of parkin.
478.18 Y Leng, et al. Carbachol stimulation induces α-synuclein translocation from plasma membrane to cytosolic vesicles in SY5Y cells.
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Society for Neuroscience Annual Meeting: COX-2 Gene Expression Parallels AD Progression
The molecular and genetic mechanisms involved in the initiation and progression of Alzheimer’s disease (AD) are poorly understood. One emerging player in the proinflammatory cycle operating in AD brain is cyclooxygenase-2 (COX)-2, an inducible prostaglandin synthase which has been repeatedly shown [independently by several laboratories] to be overexpressed in association neocortex and hippocampus afflicted with AD. Because of its pivotal importance in mediating brain inflammatory reactions, COX-2 has been a pharmacological target in human AD therapeutics. Selective nonsteroidal anti-inflammatory drugs (NSAIDS) which specifically inhibit COX-2 inhibitors, i.e., the COX-bs (rofecoxib, celecoxib, etc.) are currently being developed and used in clinical trials.
Pasinetti’s group (299.14) reported that the intensity of COX-2 gene expression in the CA3 and CA2 (but not CA-1) hippocampal pyramidal layers in AD brain increases in parallel with disease progression, and more specifically as AD progressed from questionable (CDR1) to mild clinical dementia (CDR3), [i.e., from a clinical dementia rating (CDR) which is on a scale of CDR0 (no dementia) to CDR5 (very severe dementia)]. COX-2 expression was found to be preferentially elevated in neuronal cells. At CDR5 COX-2 gene expression was increased in all three hippocampal regions (see Ho et al., 2000).
Experiments using triply transgenic mice (APPswe/PS1-A246E?hCOX-2; amyloid precursor protein-human presenilin-1-COX-2) suggested that COX-2 may have an influence on how Aβ peptide is processed. Importantly, the elevation in COX-2 gene expression preceded elevations in cytokine IL-6 and TGF-B1 gene expression at advanced CDR stages, suggesting that the upregulation of COX-2 gene expression is an early or preinflammatory event in AD staging. Pasinetti’s data therefore supported the ideas that (1) NSAIDs are efficacious because they, in part, may be exerting effects on COX-2 during the early stages of AD, (2) that specific inflammatory conditions have direct correlations with the clinical progression of AD, and (3) there is a strong correlation between internal markers in AD brain and the index of cognitive decline. Such considerations are therefore expected to be essential for the design of preventive treatment strategies.—Walter Lukiw
References: 299.14. Pasinetti GM. Brain inflammation as a function of clinical progression of Alzheimer's disease dementia: Implications for preventive anti-inflammatory strategies.
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- Luterman JD, Haroutunian V, Yemul S, Ho L, Purohit D, Aisen PS, Mohs R, Pasinetti GM. Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia. Arch Neurol. 2000 Aug;57(8):1153-60. PubMed.
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- Luterman JD, Haroutunian V, Yemul S, Ho L, Purohit D, Aisen PS, Mohs R, Pasinetti GM. Cytokine gene expression as a function of the clinical progression of Alzheimer disease dementia. Arch Neurol. 2000 Aug;57(8):1153-60. PubMed.
Society for Neuroscience Annual Meeting: Down-regulation of Transcription Factors in AD
Widespread reports of changes in RNA message abundance and specific RNA message levels in senescent cultured primary neural cells, in normal aging human brain and especially in Alzheimer’s disease-afflicted neocortex and hippocampus suggest the down-regulation of brain-specific genes during senescence, aging and in AD. To this end, a reduction in the general availability of transcription factors (TFs) and related signal transduction elements have been implicated in AD and age-related syndromes.
To further decipher changes in TF and signal transduction gene expression in AD hippocampus associated with brain aging and neurodegeneration, Lukiw et al. (301.6) simultaneously analyzed ~1200 RNA message levels using broad-spectrum commercially available cDNA array panels (Clontech part number 7852-1) and 32P-labeled cDNA probes derived from hippocampal CA1 poly A+ RNA fractions. RNA messages were isolated from a group of five pooled control and five pooled AD brains to aid in minimizing individual differences in brain gene expression patterns. Importantly, there were no significant differences in age, postmortem interval, drug or genetic history between the control and AD groups. The authors reported that AD samples showed significant decreases of threefold or more (each pSeven TF RNA message levels were found to be decreased in this study. Six (including GATA-4, BRCA1-associated, PCAF-associated 65B,LYL-1, MTF-1 and GATA-2) are known to be developmentally regulated and a different set of six required the trace element zinc (including the GATA group, LYL-1, MTF-1 and NF-KB p52). Interestingly, MTF-1, a metal regulatory element, is known to be essential in the response of the brain to potentially neurotoxic metal ion load. MTF-1 is also a major contributor to the redox state of the cell, and increases in the levels of reactive oxygen species in AD have been widely reported. In these experiments, the only TF that was found to be increased was one member of the nuclear factor-KB gene family, the NF-KB p52 subunit, which has an established role in the proliferation of the brain’s immune and inflammatory response.—Walter Lukiw
(Note: Dr. Lukiw is an author of this abstract.)
References: Abstract 301.6. Lukiw WJ, Carver LA, LeBlanc HJ, Bazan NG. Decreases in zinc-dependent transcription factor messenger RNA in Alzheimer's disease hippocampal CA1 region as analyzed by high density cDNA arrays.
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Society for Neuroscience Annual Meeting: More Potential AD Gene Loci from NIMH Study
Bertram et al. (301.7), evaluated Alzheimer’s disease (AD) candidate genes and AD chromosomal regions of interest (`30 cM) from the whole genome scans available from the National Institutes of Mental Health-Alzheimer Disease ((NIMH-AD) Genetics Initiative Program. These NIMH population samples, consisting of about 500 sibling pairs, is one of the largest AD study populations collected to date. This rather large and well characterized sample has, therefore, sufficient statistical power to score genes potentially involved in the etiopathogenesis of aging, AD and other neurodegenerative disorders.
The authors performed this genome scan analysis at three potential sites on 1000 subjects [obtained from 300 NMIH-AD participating families. In summary, these analyses revealed 16 novel, putative AD chromosomal regions of interest involving unlinked genetic loci on human chromosomes 1, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 16, 21 and X.
FASTLINK and the Sibship Disequilibrium Test (SDT; a family-based association test that can be used in the absence of parental data ) was also used to score for potential AD genetic loci in these analyses. To confirm that this approach was valid, results of LOD scoring, affected pedigree member analysis, and sib-pair analysis supported ApoE-4 as a strong risk factor for AD (previously known). A ~30 cM region on chromosome 10 showed linkage to AD with a log of the odds (LOD) score of 2-3. Interestingly, the newly discovered nicastrin gene and the gene for presenilin-2 (PS2) both lie in rather close proximity on the long arm of human chromosome 1, another potential AD locus. (See also Tanzi et al., Blacker et al).—Walter Lukiw
References: Session 301.7. Bertram DL, Blacker J, Jones D, Keeney K, Mullin S, Basu S, Yhu R, Go M, McInnis RE, Tanzi. Testing for genetic association and linkage in Alzheimer disease: Results of the NIMH study.
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Society for Neuroscience Annual Meeting: Presenilin and COX-2 Expression Induced by Oxidative Stress
The presenilin-1 and -2 (PS1, PS2) genes encode integral transmembrane proteins putatively involved in cell-cell recognition, cell-fate determination, intercellular signaling and Aβ peptide formation. Cyclooxygenase-2 (COX-2), also a membrane-associated oxidoreductase, is a key intermediary in the propagation of neuroinflammation in Alzheimer’s disease (AD).
Rogaev et al. (492.14) examined RNA message abundance for PS1, PS2 and COX-2 in: (a) gerbil hippocampus 72 hr after a single episode of cerebral ischemia; (b) hypoxic rat retina undergoing neovascularization; and (c) human neural cells in primary culture after treatment with Aβ42, NMDA and IL-1B. PS1, PS2 and COX-2 RNA message levels were quantitated, and displayed remarkably parallel induction kinetics (r212 and one to three hrs, respectively. Therefore, PS1 and COX-2 are characteristic of rapidly transduced mRNAs, while the RNA message for PS2 is not. DNA sequence analysis of the TATA-box containing PS1, PS2 and COX-2 promoters exhibited important similarities in their repertoire of transcription factor recognition sites, including those for AP2α, HIF-1 and for the proinflammatory TF triad AP1, NF-KB and STAT1/3. The human PS2 promoter contains six HIF-1 regulatory sites (consensus 5'CGTG-3') and was found to be strongly induced in neovascularization models of retinal hypoxia.
Taken together, the data suggest that the PS1, PS2, and COX-2 genes (1) are developmentally regulated, (2) share coregulated transcriptional control and that (3) expression of the PS1, PS2 and COX-2 genes may be an early neural genetic response to both acute and chronic brain stress. (See also Lukiw et al.)—Walter Lukiw
(Note: Dr. Lukiw is an author of this abstract.)
References: 492.14. Rogaev EI, Lukiw WJ, Colangelo V2, Gordon WC1, Bazan NG2. Coordinated PS1, PS2 and COX-2 gene transcription in oxidation stressed hippocampus, retina and human neural progenitor cells.
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Society for Neuroscience Annual Meeting: Chromosome Missegregation Linked to PS Mutations
Presenilin-1 and -2 (PS1, PS2) gene mutations appear to cause the majority of cases of early onset familial Alzheimer’s disease (EO-FAD). In this presentation Potter et al. (492.2) presented data that PS1 and PS2 (the PS's) have a nuclear membrane location and they may also reside, or are associated with related nuclear structures involved in cell division, chromosome segregation, nuclear apoptosis and chromosome destruction. Firstly, it was reviewed that Down's syndrome (DS) is associated with a triplicate chromosome 21 and virtually all individuals with DS develop AD pathology by age 30-40. Fibroblasts derived from FAD patients with mutant PS1 genes have often have chromosome 21 defects, including trisomy 21, and trisomy 21 is also associated with the potent cytokine IL-1 and Aβ overexpression.
Besides their putative roles in intercellular signaling and cell-fate determination, PS’s have also been shown to (1) induce apoptosis in the CNS and (2) to halt cell division in the G1 phase of the cell cycle (see Janicki and Monteiro, Am J Pathol 1999). Expression of the tumor supressor gene p53, localized to the centrosome, has been shown to decrease PS1 expression levels, and p53 mutations cause abnormal centrosome duplication and chromosome missegregation. PSs are thus implicated in the control of the cell cycle. Additional data in transgenic models showed that mutant PSs can induce chromosome mis-segregation. Taken together, the results suggested that AD is associated with a defect in the cell division cycle (at G1?) that ultimately leads to the mis-segregation of chromosomes and their disruption via the process of apoptosis and related nuclear destructive mechanisms.—Walter Lukiw
References: Session 492.2 Potter H, Geller LN, Wefes IM, Ma J. Chromosome segregation defects caused by Alzheimer presenilin mutations.
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Society for Neuroscience Annual Meeting: Role of Nicastrin-Presenilin Complexes
Presenilin-1 and -2 (PS1 and PS2) are members of a (growing) family of genes which encode polytopic integral transmembrane proteins homologous to the Notch cell surface receptors of Drosophila and the sel-12 element of the C. elegans gene (see Selkoe, Curr Opin Neurobiol 2000;10:50-57); Czech et al., Prog Neurobiol 2000;60:63-384). The PSs were reviewed to subserve putative membrane functions linked to signal transduction, neuronal development and degeneration. PS1 and PS2 behave as membrane molecular complexes; they can be cleaved internally to generate stable N- and C-terminal PS fragments (NTF/CTF). Maturation of this PS complex suggested that additional membrane-integral or peripherally associated components might be associated with this PS1/PS2 membranal complex.
Yu et al. (492.8) described the discovery of nicastrin, a novel transmembrane glycoprotein that forms high molecular weight intramembrane complexes with PS1 and PS2. It was found that suppression of nicastrin expression in C. elegans induces a subset of Notch/GLP-1 phenotypes. Nicastrin was also shown to bind to the carboxy-terminal of β-amyloid precursor protein (βAPP) and thereby modulated the production of Aβ from β-amyloid precursor protein. It was also reported that missense mutations in a highly conserved hydrophilic domain of nicastrin increased the secretion of Aβ peptides. In conclusion, PS1 or PS2 and nicastrin are thought to form high molecular weight integral membrane protein complexes which (a) may represent key components of the intramembranous proteolysis of proteins implicated in AD neuropathology (such as Notch/GLP-1 and βAPP) and (b) may have a more general role as a “secretosome” in scavenging, processing or catabolizing intramembranal and/or membrane associated peripheral proteins. (See Yu et al., Nature 2000 407.)—Walter Lukiw
References: 492.8 Yu G, Holmes E, Yang DS, Chen F, Nishimura M, Tandon A, Fraser P, St George-Hyslop P. Nicastrin—An analysis of the formation and maturation of the presenilin complexes in Alzheimer's disease.
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