Synapses, synaptic activity and intraneuronal abeta in Alzheimer's disease

Abstract

beta-Amyloid peptide accumulation plays a central role in the pathogenesis of Alzheimer's disease. Aberrant beta-amyloid buildup in the brain has been shown to be present both in the extracellular space and within neurons. Synapses are important targets of beta-amyloid, and alterations in synapses better correlate with cognitive impairment than amyloid plaques or neurofibrillary tangles. The link between beta-amyloid and synapses became even tighter when it was discovered that beta-amyloid accumulates within synapses and that synaptic activity modulates beta-amyloid secretion. Currently, a central question in Alzheimer's disease research is what role synaptic activity plays in the disease process, and how specifically beta-amyloid is involved in the synaptic dysfunction that characterizes the disease.

Keywords: Alzheimer disease; amyloid; amyloid precursor protein; neprilysin; neurodegeneration; neuron; synapse; synaptic plasticity.

Figure 1

(A) Accumulation of intraneuronal Aβ42 at early stages of AD occurs progressively in a synapse (left) and is associated with pathological alterations compared to a normal synapse (right). (B) Intraneuronal Aβ42 is released in the extracellular space following degeneration of the synapse (left). Release of intraneuronal Aβ42 into the extracellular space may contribute to the toxic spread of Aβ pathology to a nearby synapse (right).