Another piece has been added to the puzzle of how the amyloid-β peptide, which accumulates in the brains of patients with Alzheimer's disease, might cause neurological damage and memory loss.Writing in Nature Neuroscience, Snyder and colleagues describe how amyloid-β can influence the removal of NMDA (N-methyl-D-aspartate)-type glutamatergic receptors from cortical synapses.

In patients with Alzheimer's disease, the levels of amyloid-β in the brain are higher than normal, and amyloid-β forms extracellular plaques and intracellular inclusions. However, memory impairments and synaptic abnormalities are found in animal models of Alzheimer's disease before the plaques begin to form, which has led to speculation that soluble extracellular amyloid-β might be responsible for these pathological effects. But how amyloid-β might cause pathogenic changes in Alzheimer's disease has remained unclear.

As amyloid-β can reduce long-term potentiation (LTP) — a type of lasting synaptic plasticity that is thought to be associated with memory formation — Snyder et al. investigated whether amyloid-β alters signalling through NMDA receptors, which are needed for most types of LTP. In cultured cortical neurons, amyloid-β reduced the number of NMDA receptors on the cell surface at synapses, without altering the overall levels of these receptors. The reduction in receptors at the synapse was the result of an increase in endocytosis that was caused by treatment with amyloid-β.

To investigate whether a similar effect occurs in vivo, the authors looked at NMDA receptors in neurons from a mouse model of Alzheimer's disease. They found that surface expression of the NR1 subunit of NMDA receptors was much lower in cortical neurons from these mice than in neurons from control mice.

How could amyloid-β regulate the endocytosis of NMDA receptors? Amyloid-β binds to α-7 nicotinic receptors, which are found at more than 70% of cortical glutamatergic synapses, and these receptors can activate protein phosphatase 2B (PP2B). Inhibiting either α-7 nicotinic receptors or PP2B reduced the ability of amyloid-β to promote the endocytosis of NMDA receptors. One target of PP2B is the striatal enriched phosphatase (STEP), and treatment with amyloid-β reduced the phosphorylation of STEP. The authors used a dominant-negative fusion protein to provide further evidence that amyloid-β dephosphorylates and activates STEP, which can dephosphorylate NMDA receptor subunits and thereby promote their endocytosis.

Further work will be needed to pin down the exact mechanism by which amyloid-β can regulate the synaptic expression of NMDA receptors, and whether this accounts fully for the synaptic abnormalities that are found in Alzheimer's disease. Nevertheless, this finding could provide important new insight into the pathogenesis of Alzheimer's disease, as well as pointing towards potential new therapeutic targets.