Synapses and Alzheimer's Disease

Alzheimer's disease (AD) is a major cause of dementia in the elderly. Pathologically, AD is characterized by the accumulation of insoluble aggregates of A beta-peptides that are proteolytic cleavage products of the amyloid-beta precursor protein (plaques) and by insoluble filaments composed of hyperphosphorylated tau protein (tangles). Familial forms of AD often display increased production of A beta peptides and/or altered activity of presenilins, the catalytic subunits of gamma-secretase that produce A beta peptides. Although the pathogenesis of AD remains unclear, recent studies have highlighted two major themes that are likely important. First, oligomeric A beta species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side. Second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. The mechanisms underlying these processes are beginning to be elucidated, and, although their relevance to AD remains debated, understanding these processes will likely allow new therapeutic avenues to AD.