Apolipoprotein E and amyloidogenesis

Blas Frangione, Eduardo M. Castaño, Thomas Wisniewski, Jorge Ghiso, Frances Prelli, Ruben Vidal

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Abstract

Alzheimer's amyloid β-protein (Aβ) is a modified, pathogenic form of a constitutive host protein, soluble amyloid β-protein (sAβ). Both are conformational isomers encoded by the gene for the β-amyloid precursor protein (APP), located on chromosome 21. sAβ and Aβ have identical sequence but are thought to differ in their secondary structure and physicochemical properties, hence they are conformational isomers. sAβ is easily degraded, while Aβ is partially resistant. Aβ has a high β-pleated sheet content, while sAβ is thought to be more random-coil and/or α-helical. Aβ, unlike sAβ, adopts an amyloidogenic conformation, forms aggregates and gives rise to fibrils. Most early-onset forms of Alzheimer's disease (AD) have been linked to mutations of the presenilin 1, presenilin 2 or APP genes, located on chromosomes 14, 1 and 21, respectively. Their relationship to amyloidogenesis is being investigated. On the other hand, the major risk factor for the most common form, sporadic and familial late-onset AD, is the presence of the apoE ε4 allele. Recent studies have shown that a 10 kDa C-terminal fragment of apoE is complexed to Aβ in neuritic plaques and that apoE isoforms can modulate amyloid formation in vitro. Moreover, thrombin cleavage of apoE generates a similar C-terminal fragment that can form amyloid-like fibrils. Thus neuritic plaques may contain both Aβ and apoE amyloid fibrils. AD can be neuropathologically defined by the presence of several interacting proteins that can adopt an amyloidogenic conformation. This has led us to hypothesize that in AD, amyloidosis may be reactive rather than causative.

Original languageEnglish (US)
Pages (from-to)132-145
Number of pages14
JournalCIBA Foundation Symposia
Issue number199
StatePublished - Dec 1 1996
Externally publishedYes

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    Frangione, B., Castaño, E. M., Wisniewski, T., Ghiso, J., Prelli, F., & Vidal, R. (1996). Apolipoprotein E and amyloidogenesis. CIBA Foundation Symposia, (199), 132-145.