Publication: Alzheimer ß-amyloid peptides normal and abnormal localization
Authors
Takahashi, R.H. ; Nam, E.E. ; Edgar, M. ; Gouras, G.K.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
Alzheimer's disease (AD) neuropathology is
characterized by accumulation of “senile” plaques (SPs)
and neurofibrillary tangles (NFTs) in vulnerable brain
regions. SPs are principally composed of aggregates of
up to 42/43 amino acid ß-amyloid (Aß) peptides. The
discovery of familial AD (FAD) mutations in the genes
for the amyloid precursor protein (APP) and presenilins
(PSs), all of which increase Aß42 production, support
the view that Aß is centrally involved in the
pathogenesis of AD. Aß42 aggregates readily, and is
thought to seed the formation of fibrils, which then act
as templates for plaque formation. Aß is generated by
the sequential intracellular cleavage of APP by ßsecretase
to generate the N-terminal end of Aß, and
intramembranous cleavage by g-secretase to generate the
C-terminal end. Cell biological studies have
demonstrated that Aß is generated in the ER, Golgi, and
endosomal/lysosomal system. A central question
involving the role of Aß in AD concerns how Aß causes
disease and whether it is extracellular Aß deposition
and/or intracellular Aß accumulation that initiates the
disease process. The most prevalent view is that SPs are
composed of extracellular deposits of secreted Aß and
that Aß causes toxicity to surrounding neurons as
extracellular SP. The recent emphasis on the intracellular
biology of APP and Aß has led some investigators to
consider the possibility that intraneuronal Aß may
directly cause toxicity. In this review we will outline
current knowledge of the localization of both
intracellular and extracellular Aß.
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