Regulation of Alzheimer beta-amyloid precursor trafficking and metabolism

Alzheimer's disease (AD) is characterized by the intracranial accumulation of the 4 kDa amyloid-beta peptide (Abeta), following proteolysis of a approximately 700-amino acid, integral membrane precursor, the Alzheimer amyloid precursor protein (APP). The best evidence causally linking APP to AD has been provided by the discovery of mutations within the APP coding sequence that segregate with disease phenotypes in autosomal dominant forms of familial AD (FAD). Though FAD is rare ( < 10% of all AD), the hallmark features (amyloid plaques, neurofibrillary tangles, synaptic and neuronal loss, neurotransmitter deficits and 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 the enhanced generation or aggregability of Abeta, 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 Abeta. Epidemiological studies indicate that postmenopausal women on estrogen replacement therapy (ERT) have their relative risk of developing SAD diminished by about one third as compared with age-matched women not receiving ERT [M.X. Tang, D. Jacobs, Y. Stern, K. Marder, P. Schofield, B. Gurland, H. Andrews, R. Mayeux, Effect of estrogen during menopause on risk and age at onset of Alzheimer's disease, Lancet 348 (2000) 429432]. Because of the key role of cerebral Abeta accumulation in initiating AD pathology, it is most attractive that estradiol might modulate SAD risk or age-at-onset by inhibiting Abeta accumulation. A possible mechanistic basis for such a scenario is reviewed here.