J. Neurochem. (2011) 119, 664–672.AbstractStriatal‐Enriched protein tyrosine Phosphatase of MW 61 kDa (STEP61) is a protein tyrosine phosphatase recently implicated in the pathophysiology of Alzheimer’s disease (AD). STEP61 is elevated in human AD prefrontal cortex and in the cortex of several AD mouse models. The elevated levels of active STEP61 down‐regulate surface expression of GluN1/GluN2B (formerly NR1/NR2B) receptor complexes, while genetically reducing STEP levels rescues both the biochemical and cognitive deficits in a triple transgenic AD mouse model (3xTg‐AD). Here, we show that increased STEP61 also plays a role in beta amyloid (Aβ)‐mediated internalization of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐(AMPA) receptor (AMPAR) subunits GluA1/GluA2 (formerly GluR1/GluR2). We purified Aβ oligomers and determined that oligomers, but not monomers, lead to endocytosis of GluA1/GluA2 receptors in cortical cultures. The decrease in GluA1/GluA2 receptors is reversed in the progeny of STEP knock‐out (KO) mice crossed with Tg2576 mice, despite elevated levels of Aβ. These results provide strong support for the hypothesis that STEP61 is required for Aβ‐mediated internalization of GluA1/GluA2 receptors.