Activity-dependent synapse modulation and the pathogenesis of Alzheimer disease

During normal development of the nervous system, a major reduction occurs in the initially excessive number of neurons and synapses. This "pruning" process is heavily influenced by patterns of electrical activity in the synaptic circuits being pruned. Many of the cell biological and molecular mechanisms involved in this activity-dependent modification of nervous system structure and function have been explicated, and the area is one of intense study. Similarly, an explosive increase has occurred in knowledge about the molecular pathogenesis of Alzheimer disease (AD). There are significant mechanistic commonalities between the normal neurodevelopmental process and development of AD. We hypothesize that abnormalities in neural activity patterns, or in the coupling between neural activity and maintenance of neurons and synaptic circuits, may be a key determinant in the pathogenesis of AD that is late in onset, sporadic in nature, and in which the genes for the presenilins and the beta amyloid precursor protein are normal. Behavioral data suggests that an active, socially engaged life-style may be associated with a reduced risk for AD. If so, mechanisms linking neural activity with synaptic circuit integrity are probably involved and provide a target for ameliorative pharmacological intervention.