Abstract
The central pathological cause of Alzheimer disease (AD) is hypothesized to be an excess of beta-amyloid (Abeta) which accumulates into toxic fibrillar deposits within extracellular areas of the brain. These deposits disrupt neural and synaptic function and ultimately lead to neuronal degeneration and dementia. In addition to the pathological roles attributed to Abeta, evidence from our laboratory would suggest that Abeta serves a physiological role in the modulation of CRE-directed gene expression. This commentary also highlights some of the pathological consequences of the accumulation of intracellular Abeta. Finally it discusses the impact of cortical Abeta burden on transmitter-specific synaptic numbers as well as the generation of dystrophic neurites. The fundamental thesis of my proposal is that the Abeta pathology seen in AD is a continuous process from an initial abnormal Abeta intracellular accumulation to the well-established extracellular Abeta aggregation, culminating in the formation of amyloid plaques and dystrophic neurites.