Abstract: Series 99, Lecture 2

The Harvey Lectures Series 99 (2003—2004)

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Lecture #2: Thursday, November 20, 2003 — Time and Location

Toward a Remembrance of Things Past: Deciphering Alzheimer's Disease

Dennis J Selkoe, MD

Professor of Neurology
Vincent and Stella Coates Professor of Neurologic Diseases

Harvard Medical School

Boston, Massachusetts

A remarkable rise in life expectancy during the past century has made Alzheimer’s disease the most common form of progressive intellectual failure in humans. Alzheimer patients lose their most human qualities — reasoning, abstraction, language and memory. Analyses of the classical brain lesions that Alzheimer described, the senile (amyloid) plaques and the neurofibrillary tangles, preceded and guided the search for genetic alterations that could underlie the disease. Four genes have been implicated to date, and their mutations or polymorphisms cause progressive accumulation of the amyloid ß-protein and subsequent synaptic dysfunction in brain regions serving memory and cognition. Studies of two of the Alzheimer-causing genes — presenilin 1 and APP — led to the recognition of an intersection between early development and late-life neurodegeneration. Presenilin is an unprecedented intramembrane aspartyl protease that cleaves APP, Notch and numerous other membrane substrates within the lipid bilayer. Elucidating how presenilin processes proteins is important for understanding cell fate determination and other signaling pathways. Knowledge of the genotype-to-phenotype conversions of familial Alzheimer’s disease has led to the development of specific therapeutic strategies to chronically lower amyloid ß-protein. While hard work lies ahead, the movement of cell biological research on Alzheimer’s disease to the clinic exemplifies how reductionist biology can be applied to disorders of the most complex of biological systems, the human cerebral cortex.