Soluble Aβ inhibits specific signal transduction cascades common to the insulin receptor pathway

Numerous studies have now shown that the amyloid beta-protein (A beta),the principal component of cerebral plaques in Alzheimer disease, rapidly and potently inhibits certain forms of synaptic plasticity. The amyloid (or A beta) hypothesis proposes that the continuous disruption of normal synaptic physiology by A beta contributes to the development of Alzheimer disease. However, there is little consensus about how A beta mediates this inhibition at the molecular level. Using mouse primary hippocampal neurons, we observed that a brief treatment with cell-derived, soluble, human A beta disrupted the activation of three kinases (Erk/MAPK, CaMKII, and the phosphatidylinositol 3-kinase-activated protein Akt/protein kinase B) that are required for long term potentiation, whereas two other kinases (protein kinase A and protein kinase C) were stimulated normally. An antagonist of the insulin receptor family of tyrosine kinases was found to mimic the pattern of A beta-mediated kinase inhibition. We then found that soluble A beta binds to the insulin receptor and interferes with its insulin-induced autophosphorylation. Taken together, these data demonstrate that physiologically relevant levels of naturally secreted A beta interfere with insulin receptor function in hippocampal neurons and prevent the rapid activation of specific kinases required for long term potentiation.