Activation of the Amyloid Cascade in Apolipoprotein E4 Transgenic Mice Induces Lysosomal Activation and Neurodegeneration Resulting in Marked Cognitive Deficits

• DOI: 10.1523/jneurosci.5633-07.2008
• Publication Date: 2008-04-30T16:28:19Z
• Authors: Haim Belinson; Dimitri Lev; Eliezer Masliah; Daniel M. Michaelson
• Keywords: Apolipoprotein E; Amyloid (mycology)

The allele E4 of apolipoprotein E (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, is associated histopathologically with elevated levels brain amyloid. This led to suggestion that pathological effects apoE4 are mediated by cross-talk interactions amyloid β peptide (Aβ), which accentuate cascade. mechanisms underlying Aβ-mediated unknown. We have shown recently inhibition Aβ-degrading enzyme neprilysin in brains wild-type apoE3 and mice results rapid similar elevations their total Aβ levels. However, nucleation aggregation these were markedly affected apoE genotype specifically enhanced mice. presently used paradigm analyze neuropathological cognitive induced after activation revealed stimulates isoform degeneration hippocampal CA1 neurons entorhinal septal neurons, accompanied accumulation intracellular lysosomal activation. Furthermore, occurrence pronounced deficits ApoE4 These findings provide first vivo evidence regarding cellular cross talk between Aβ, as well a novel model system neurodegeneration uniquely suitable studying early stages cascade thereon apoE4.