Alzheimer ß-amyloid peptides: normal and abnormal localization

R.H. Takahashi1, E.E. Nam1, M. Edgar1 and G.K. Gouras1,3

1Department of Neurology and Neuroscience and 2Department of Pathology, Weill Medical College of Cornell University, and 3Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, USA

Offprint requests to: Dr. Gunnar K. Gouras, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, 525 East 68th Street New York, NY 10021, USA. e-mail: gkgouras@med.cornell.edu

Summary. 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 ß-secretase 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. Histol. Histopathol. 17, 239-246 (2002)

Key words: Alzheimer's disease, Amyloid precursor protein (APP), Beta-amyloid (Aß), Neuropathology, Cell biology

DOI: 10.14670/HH-17.239