Activities
Dennis J. Selkoe
APP, Presenilin and the Origin of Synaptic Failure in AD
A remarkable rise in life expectancy during the past century has made Alzheimer’s disease (AD) the most common form of progressive intellectual failure in humans. Patients with AD lose their most human qualities - reasoning, abstraction, language and memory. Analyses of the classical brain lesions that Alois Alzheimer described, the senile (amyloid) plaques, and the neurofibrillary tangles, preceded and has guided the search for genetic alterations that could underlie AD. Four genes have been unequivocally implicated to date in inherited forms of AD, and mutations or natural variations in these genes cause excessive accumulation of the amyloid ß-protein and subsequent neuronal degeneration in brain regions important for memory and cognition. This understanding of the genotype-to-phenotype conversions of familial AD, coupled with cell culture and animal models of the process, has led to the development of specific pharmacological strategies to lower amyloid ß-protein levels as a way of treating or preventing all forms of the disease. While hard work lies ahed, the movement of basic research on AD to the clinic represents a triumph of reductionist biology applied to the most complex of all biological systems, the human cerebral cortex.