The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides Aβ, such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates Aβ clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with Aβ rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other Aβ binding proteins, including ACT and apo J can inhibit or promote Aβ oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.
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Citation / Publisher Attribution
International Journal of Alzheimer’s Disease, v. 2012, art. 489428
Scholar Commons Citation
Potter, Huntington and Wisniewski, Thomas, "Apolipoprotein E: Essential Catalyst of the Alzheimer Amyloid Cascade" (2012). Molecular Medicine Faculty Publications. 18.
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