By Minji Kim, Alice Lu, and Rudy Tanzi.

 

David Holtzman, Washington University, St. Louis, Missouri, discussed the roles of ApoE and its three major isoforms—ε2, 3, and 4—on Aβ aggregation and clearance in FAD mutant APP mice expressing various ApoE isoforms. Hippocampal Aβ levels were suppressed in PDAPP transgenic mice expressing human ApoE isoforms, while the absence of ApoE resulted in altered half-life (50 percent increase) of interstitial fluid Aβ (normal half-life is ~2 hours). Holtzman suggested that ApoE plays a role in the transport and clearance of soluble Aβ. He also showed a role of LDLR (but not LRP) in regulating ApoE levels in the CNS of human ApoE knock-in mice. Finally, he presented data showing that ABCA1, which normally lipidates apoprotein with HDL, also lipidates ApoE in CNS. In ABCA1-/- mice, ApoE levels were decreased while ApoE mRNA levels were unchanged. Holtzman suggested that the lipidation state of ApoE by ABCA1 may influence amyloidogenesis.

Berislav Zlokovic, University of Rochester, New York, highlighted the importance of regulation of Aβ clearance across the BBB via efflux of soluble Aβ by LRP binding and its re-entry into brain via RAGE in AD and other neurodegenerative disorders. He showed that Dutch/Iowa mutant form Aβ possessed low affinity for LRP1 and was poorly cleared in the transgenic mouse. When APPswe+/- mice were treated from 6-9 months with secreted LRP (sLRP) daily (40 ug/kg, S.C.), performance on a visual memory task was improved. The mechanism of action is believed to involve sLRP binding Aβ in plasma, preventing re-entry into brain. In addition, Zlokovic made the point that RAGE-dependent Aβ transport induces neurovascular stress, while RAGE blockage improved cerebral blood flow in Tg2576 mouse. A screen of CHO cells showed that tertiary amides could be used to block RAGE-Aβ interactions with high affinity, thus suggesting prospects for therapeutic intervention.

Louis Hersh, University of Kentucky, Lexington, presented recent studies of NEP and IDE as therapeutic targets for AD based on enhancing Aβ degradation. Neprilysin and IDE activities are decreased in AD brain, and both enzymes are sensitive to oxidation. Neprilysin contains steroid hormone response elements, and ovariectomy decreased neprilysin activity in mice after 45 days. This could be rescued with estrogen. Lentiviral transduction of NEP into CHO cells lowered extracellular Aβ42, and its administration into APP transgenic mice led to a decrease in Aβ deposits and dissolution of preformed amyloid deposits. Hersh also showed evidence that dynorphin B9 could allosterically induce IDE catalytic activity specifically toward Aβ without changing its insulin-degrading activity, thus supporting IDE as an attractive therapeutic target. Additionally, he provided data that a newly identified small molecule, NGX96992, increased Aβ-degrading activity of IDE twofold.

Matthew Townsend, Brigham and Women’s Hospital, Boston, presented data regarding the neutralizing effect of the inositol derivative, AZD-103, on inhibition of long-term potentiation (LTP) by cell-derived oligomeric Aβ. AZD-103 does not destabilize Aβ oligomers but abrogates their effects on LTP before they come into contact with cells (not afterward). One possibility is that AZD-103 prevents Aβ oligomers from binding synaptic membranes. The rescue of LTP by AZD-103 was specific to Aβ and AZD-103 showed no overt toxicity, suggesting its potential benefit for AD therapy.

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