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In Alzheimer’s disease, Aβ-oligomers activate STEP by two parallel pathways. (1) Aβ-oligomers bind to α7-nicotinic receptors and cause calcinuerin-dependent dephosphorylation of STEP at its KIM domain (2) Aβ-oligomers block the proteasome-mediated degradation of STEP and increase STEP levels. Both these events lead to increase in STEP function and increased endocytosis of NMDA and AMPA receptors causing cognitive dysfunction.
