Amyloid-beta as a Modulator of Synaptic Plasticity

Alzheimer's disease is associated with synapse loss, memory dysfunction, and pathological accumulation of amyloid-beta (A beta) in plaques. However, an exclusively pathological role for A beta is being challenged by new evidence for an essential function of A beta at the synapse. A beta protein exists in different assembly states in the central nervous system and plays distinct roles ranging from synapse and memory formation to memory loss and neuronal cell death. A beta is present in the brain of symptom-free people where it likely performs important physiological roles. New evidence indicates that synaptic activity directly evokes the release of A beta at the synapse. At physiological levels, A beta is a normal, soluble product of neuronal metabolism that regulates synaptic function beginning early in life. Monomeric A beta(40) and A beta(42) are the predominant forms required for synaptic plasticity and neuronal survival. With age, some assemblies of A beta are associated with synaptic failure and Alzheimer's disease pathology, possibly targeting the N-methyl-D-aspartic acid receptor through the nicotinic acetylcholine receptor, mitochondrial A beta alcohol dehydrogenase, and cyclophilin D. But emerging data suggests a distinction between age effects on the target response in contrast to the assembly state or the accumulation of the peptide. Both aging and A beta independently decrease neuronal plasticity. Our laboratory has reported that A beta, glutamate, and lactic acid are each increasingly toxic with neuron age. The basis of the age-related toxicity partly resides in age-related mitochondrial dysfunction and an oxidative shift in mitochondrial and cytoplasmic redox potential. In turn, signaling through phosphorylated extracellular signal-regulated protein kinases is affected along with an age-independent increase in phosphorylated cAMP response element-binding protein. This review examines the long-awaited functional impact of A beta on synaptic plasticity.