Regulation of alzheimer beta-amyloid precursor trafficking and metabolism.

Abstract

Alzheimer’s disease (AD) is characterized by the intracranial accumulation of the 4 kDa amyloid-ß peptide (Aß), following proteolysis of a ~700-amino acid, integral membrane precursor, the Alzheimer amyloid precursor protein (APP). The best evidence causally linking APP to Alzheimer’s disease has been provided by the discovery of mutations within the APP coding sequence that segregate with disease phenotypes in autosomal dominant forms of familial Alzheimer’s disease (FAD). Though FAD is rare (<10% of all AD), the hallmark features, amyloid plaques, neurofibrillary tangles, synaptic and neuronal loss, neurotransmitter deficits, dementia, are indistinguishable when FAD is compared with typical, common, “non-familial”, or sporadic, AD (SAD). Studies of some clinically relevant mutant APP molecules from FAD families have yielded evidence that APP mutations can lead to enhanced generation or aggregability of Aß, consistent with a pathogenic role in AD. Other genetic loci for FAD have been discovered which are distinct from the immediate regulatory and coding regions of the APP gene, indicating that defects in molecules other than APP can also specify cerebral amyloidogenesis and FAD. To date, all APP and non-APP FAD mutations can be demonstrated to have the common feature of promoting amyloidogenesis of Aß.KeywordsAmyloid Precursor Protein ProcessingAmyloid Precursor Protein GeneAmyloid Precursor Protein MutationAmyloid Precursor Protein CleavageCerebral AmyloidosisThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.