The role of synaptic activity in the regulation of amyloid beta levels in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia. Accumulation of amyloid-beta (A beta) peptides is regarded as the critical component associated with AD pathogenesis, which is derived from the amyloid precursor protein (APP) cleavage. Recent studies suggest that synaptic activity is one of the most important factors that regulate A beta levels. It has been found that synaptic activity facilitates APP internalization and influences APP cleavage. Glutamatergic, cholinergic, serotonergic, leptin, adrenergic, orexin, and gamma-amino butyric acid receptors, as well as the activity-regulated cytoskeleton-associated protein (Arc) are all involved in these processes. The present review summarizes the evidence for synaptic activity-modulated A beta levels and the mechanisms underlying this regulation. Interestingly, the immediate early gene product Arc may also be the downstream signaling molecule of several receptors in the synaptic activity-modulated A beta levels. Elucidating how A beta levels are regulated by synaptic activity may provide new insights in both the understanding of the pathogenesis of AD and in the development of therapies to slow down the progression of AD. (C) 2014 Elsevier Inc. All rights reserved.