Last month at the feet of Germany’s tallest mountain, the Zugspitze, German Alzheimer disease researchers met with colleagues from both sides of the Atlantic to exchange their latest data on research topics ranging from the APP secretases to tau and other topics relevant to AD pathogenesis and therapy development. Having started 6 years ago as the annual retreat for the members of a priority program project by the Deutsche Forschungsgemeinschaft (DFG), the conference drew 90 participants this year. Initiated by Christian Haass of Ludwig-Maximilians-University, Munich, and managed jointly by Haass and Gerd Multhaup at Free University of Berlin, the priority program focused on the cell biology of AD, and has extended government funds to a network of up to 13 German AD labs. Since its inception in 2000, the program has helped broaden the base of AD labs across the country from three major sites that had existed in the late 1990s in Heidelberg, Hamburg, and Munich. By all accounts, the program has increased the visibility of German AD research, in part by supporting young researchers as they set up their own labs, and in part by fostering a German peer group that tries to emphasize a sense of collegiality and cooperation over work in isolation. The program’s reviewers are international. One of them, Peter St. George-Hyslop of the University of Toronto, Canada, went as far as to say that in his estimation, this priority program (or RfA in the U.S.) is the most productive worldwide program working on AD at this time. DFG priority programs expire after 6 years and are not renewable. This one will run out next month, and its history and detailed research results will appear later this year in a special issue of the journal Neurodegenerative Diseases.

Beyond featuring new findings on the γ-secretase complex, the conference showcased a broader cell biology of regulated intramembrane proteolysis by aspartyl proteases. α cleavage of APP emerged from the shadows of the more heavily studied β and γ cleavages, and new studies highlighted its exquisite regulation. APP transport and interactions between amyloid and tau drew attention, as did new mouse models of tau and mutant APP knock-in mice. Scientists advanced new modulators of amyloid β’s effect on synaptic function, new ways of studying Ab oligomers, and discussed the interplay between lipids and APP processing. Others told of the search for better NSAIDs, and offered the latest update on the Swiss patients in Elan’s aborted AN1792 immunotherapy trial.

Before the science started, however, Haass introduced a new prize in the field. The German Hans and Ilse Breuer Stiftung is a family foundation that has agreed to take over funding the Eibsee conference as an annual platform for German AD research. The foundation also committed funds for graduate student stipends and for an annual “Alzheimer-Forschungspreis.” Selected by an international jury, the prize rewards a German AD researcher with $100,000 of unrestricted research money. Its size equals that of the Potamkin Prize awarded since 1988 at the annual meeting of the American Academy of Neurology. The Potamkin Prize arguably has become the most prestigious award for AD research in the U.S. and is funded by a family foundation in memory of Luba Potamkin, a businesswoman diagnosed with dementia in 1978. Similarly, the Breuers decided to do something about Alzheimer disease after watching the suffering of their mother Ilse. The inaugural prize went to Harald Steiner, at the LMU, for his research on γ-secretase. (Steiner is a trainee of Haass’, who noted that he abstained from the prize selection process.) In Germany, people still look mostly to the government for research funding, and the scientists at the conference clearly hoped that the Breuers’ lead would inspire additional private philanthropy in their country.

Below are excerpts of the presentations and discussions:

Synapses: Duress and Relief
After recapping some milestones in AD research, Dennis Selkoe of Brigham and Women’s Hospital, Boston, started off the science by saying that a key challenge in current AD research has become to understand precisely what it is that subverts the function of certain synapses at the earliest stage of disease. Unsurprisingly for followers of the field, Selkoe suspects that Aβ oligomers, flowing in interstitial spaces, reach the synaptic cleft and interact with components of the postsynaptic machinery to throw off synaptic transmission and start disease cascades. The Alzforum has followed the evolving story of how preparations enriched for Aβ oligomers are thought to disrupt LTP in cultured brain slices and interfere with learning (Wang et al., 2002; Walsh et al., 2002; Cleary et al., 2005; Townsend et al., 2006). New developments reported at the Eibsee concern ongoing confocal microscopy studies that aim to visualize what oligomers do to dendritic spines of fluorescently labeled neurons. For example, Ganesh Shankar, working with Selkoe and Bernardo Sabatini at Harvard Medical School, is finding that picomolar quantities of secreted oligomer fractions separated by size exclusion chromatography cause a reduction in the density of spines on dendrites of cultured rat hippocampal slices. The dendrites stayed in place throughout the experiment but were no longer studded with spines a few days after oligomer application. Spine numbers began to drop the day after oligomer exposure and recovered once the oligomers were washed out, Selkoe said. Anti-Aβ antibodies restored spine number, he added, much like they appear to rescue previously observed oligomer effects on LTP in rats (Klyubin et al., 2005).

This is among the first studies to note how spines wither under direct exposure of Aβ by using a combination of diOlistic “gene gun” labeling and confocal microscopy. Other groups are using these methods to examine spines in transgenic mice. Researchers led by Floyd Bloom are noticing spine loss early on in the dentate gyrus of PDAPP mice (see SfN conference story) and similar results using Golgi impregnation are published (see Jacobsen et al., 2006). While imaging hippocampal slices of two different mutant APP- and PS1 transgenic mouse strains, scientists led by Michael Shelanski at Columbia University, New York, also noticed a dearth of spines, as well as swollen dendrites (Moolman et al., 2004). The spines in the amyloid transgenic strains looked different, with longer necks and larger heads, Shelanski said. Dendritic spines look similarly altered in some mouse models of inherited mental retardation. At the Eibsee, Shelanski showed diOlistic staining of spines of an AD patient and an 89-year-old person who had died after aging normally. (This kind of spine imaging works only in freshly fixed tissue, not in stored samples from brain banks that have been in fixatives for long periods of time, Shelanski noted.) The AD patient appeared only to have had about half of the dendritic area and number of spines as did the control, suggesting that, in this regard, the transgenic mice model AD reasonably well.

Shelanski reported on his group’s search for agents that might reverse the detrimental effects of Aβ oligomers on hippocampal synapses. He believes that factors that boost signaling through the cyclic AMP-PKA CREB signaling pathway could do the trick. (Pioneered by Eric Kandel, this pathway is thought to underlie memory processes.) Prior work had shown that rolipram—an inhibitor of phosphodiesterase 4 (PDE4) that prevents breakdown of cyclic AMP—can improve some forms of memory in mice (Barad et al., 1998). Rolipram also reverses the LTP deficit in hippocampal slices, as well as learning and memory deficits of APP/PS1 transgenic mice (Gong et al., 2004). Interestingly, once the mice had received a course of the drug, they kept performing better for several months without further treatment, as if the CREB pathway had been reset for the long term, Shelanski noted. However, efforts in biotechnology companies to bring new PDE4 inhibitors without the gastrointestinal side effects of rolipram to market have not yet succeeded.

Shelanski’s newer work takes a different tack toward the same goal of counteracting Aβ’s effect on synaptic function. It focuses on proteasome degradation, and specifically on ubiquitin C-terminal hydrolase-L1 (UCH-L1). This neuronal enzyme recycles ubiquitin, making it available for re-use in further cycles of tagging and targeted degradation of waste proteins in the protein grinder. UCH-L1 is known for its association with rare cases of Parkinson disease (e.g., Lincoln et al., 1999). It rarely comes up in AD research, except in one study that reported a down-regulation in brains of sporadic AD cases (Choi et al., 2004). Other data have suggested that it improves LTP induction in the sea slug Aplysia.

This and other hints led Shelanski’s team to develop a membrane-permeable version of UCH-L1 that enabled them to manipulate its concentration inside neurons. Called TAT-HA-UCH-L1, the construct exploits an HIV protein that induces micropinocytosis at lipid rafts and thus ferries the enzyme across the cell membrane. Much like rolipram, TAT-HA-UCH-L1 restored LTP in young APP/PS1 double-transgenic mice, Shelanski reported. It also normalized basal synaptic transmission in older transgenic mice and rescued the spine loss in their hippocampal slices, as well as in Aβ-treated slices of wild-type rodents. The reverse was also true; that is, Aβ interfered with the activity of UCH-L1 and reduced availability of mono-ubiquitin.

How would Aβ interact with UCH-L1? Shelanski believes it does so indirectly, through signaling from the outside. In any event, the added UCH-L1 propped up proteasome function either by freeing up more mono-ubiquitin, or perhaps by dimerizing and acting as a ubiquitin ligase (Liu et al., 2002). On this question, Shelanski suspects primarily the first function, since a mutation in the UCH-L1 hydrolase domain abolished its ability to restore LTP. Boosting UCH-L1 function could serve as a therapy in its own right or together with amyloid-lowering approaches, Shelanski noted. The TAT-HA-UCH-L1 construct itself won’t become a drug because it would require injection and, as a protein, could trigger an unwanted antibody response. Instead, this research serves to inform the search for small molecules, Shelanski said.—Gabrielle Strobel.


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News Citations

  1. Translational Biomarkers in Alzheimer Disease Research, Part 5

Paper Citations

  1. . Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 2002 Jan 11;924(2):133-40. PubMed.
  2. . Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002 Apr 4;416(6880):535-9. PubMed.
  3. . Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci. 2005 Jan;8(1):79-84. PubMed.
  4. . Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol. 2006 Apr 15;572(Pt 2):477-92. PubMed.
  5. . Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat Med. 2005 May;11(5):556-61. PubMed.
  6. . Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5161-6. Epub 2006 Mar 20 PubMed.
  7. . Dendrite and dendritic spine alterations in Alzheimer models. J Neurocytol. 2004 May;33(3):377-87. PubMed.
  8. . Rolipram, a type IV-specific phosphodiesterase inhibitor, facilitates the establishment of long-lasting long-term potentiation and improves memory. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):15020-5. PubMed.
  9. . Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest. 2004 Dec;114(11):1624-34. PubMed.
  10. . Low frequency of pathogenic mutations in the ubiquitin carboxy-terminal hydrolase gene in familial Parkinson's disease. Neuroreport. 1999 Feb 5;10(2):427-9. PubMed.
  11. . Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. J Biol Chem. 2004 Mar 26;279(13):13256-64. PubMed.
  12. . The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell. 2002 Oct 18;111(2):209-18. PubMed.

Other Citations

  1. Potamkin Prize

External Citations

  1. Neurodegenerative Diseases
  2. Hans and Ilse Breuer Stiftung

Further Reading