Figure 1a. Aβ-induced internalization of synaptic NMDA and AMPA receptors.

Soluble Aβ oligomers promote receptor endocytosis, reducing the density of the receptors at the synapses. Aβ is secreted into the synaptic cleft via sequential cleavage of presynaptic amyloid precursor protein (APP) (internally or at the cell surface) by β-secretase and γ-secretase or gains entry from outside the synapse. The accumulation of Aβ oligomers in the synaptic cleft leads to reduced NMDA and AMPA receptor density in synapses, leading to attenuated long-term potentiation (LTP) and neurotransmission. While Aβ oligomers may play a normal role in controlling LTP, accelerated synaptic accumulation of Aβ oligomers (for example, due to familial Alzheimer's disease [AD] gene mutations) may lead to a toxic gain of function and cognitive decline. Aβ₄₂, amyloid-β-protein 42-mer; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-d-aspartic acid.