Aβ-Mediated NMDA Receptor Endocytosis in Alzheimer's Disease Involves Ubiquitination of the Tyrosine Phosphatase STEP₆₁

Abstract

Amyloid ␤ (A␤) is involved in the etiology of Alzheimer's disease (AD) and may contribute to cognitive deficits by increasing internalization of ionotropic glutamate receptors. Striatal-enriched protein tyrosine phosphatase 61 (STEP 61 ), which is targeted in part to the postsynaptic terminal, has been implicated in this process. Here we show that STEP 61 levels are progressively increased in the cortex of Tg2576 mice over the first year, as well as in prefrontal cortex of human AD brains. The increased STEP 61 was associated with greater STEP activity, dephosphorylation of phospho-tyr 1472 of the NR2B subunit, and decreased NR1 and NR2B subunits on neuronal membranes. Treatment with A␤-enriched medium also increased STEP 61 levels and decreased NR1/NR2B abundance in mouse cortical cultures as determined by biotinylation experiments. In STEP knock-out cultures, A␤ treatment failed to induce NMDA receptor internalization. The mechanism for the increase in STEP 61 levels appears to involve the ubiquitin proteasome system. Blocking the proteasome resulted in elevated levels of STEP 61 . Moreover, STEP 61 -ubiquitin conjugates were increased in wild-type cortical slices upon A␤ treatment as well as in 12 month Tg2576 cortex. These findings reveal a novel mechanism by which A␤-mediated accumulation of STEP 61 results in increased internalization of NR1/NR2B receptor that may contribute to the cognitive deficits in AD.

Cocaine-Induced Changes of Synaptic Transmission in the Striatum are Modulated by Adenosine A2A Receptors and Involve the Tyrosine Phosphatase STEP

“…STEP mediates AMPA and NMDA receptor subunit endocytosis through tyrosine dephosphorylation of their subunits (Zhang et al, 2008;Zhang et al, 2010Zhang et al, , 2011Kurup et al, 2010). In agreement with a recent study (Sun et al, 2013), we found that cocaine reduced the phosphorylation level of the NMDAR subunit GluN2B, an effect prevented by ZM241385 and absent in stA 2A RKO.…”

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

“…Additionally, eNMDAR-mediated increases in NO generation, tau protein, tau hyperphosphorylation, and caspase-3 activity that we found in response to oligomerized Aβ argue that these early molecular events presage the loss of synapses that we observed hours later. Prior experiments had shown that after acute exposure to Aβ (10,32,63), other synaptic events also may occur, such as internalization via endocytosis of postsynaptic receptors to account for a decrease in mEPSC amplitude. However, this mechanism alone would not adequately account for the decrease in mEPSC frequency (but not amplitude) that we observed after chronic Aβ exposure in the hAPP-J20 hippocampus and that was reversed, at least partially, with prolonged memantine treatment.…”

Metabotropic NMDA receptor function is required for β-amyloid–induced synaptic depression

“…S4). In line with this scenario, the Aβ-dependent endocytosis of NMDARs requires phosphatase activity, and tyrosine dephosphorylation of GluN2B correlates with GluN1/GluN2B endocytosis (46,47). Interestingly, EphB2, a receptor tyrosine kinase that selectively controls the synaptic localization and function of GluN2B-containing NMDARs in mature neurons (48), has been implicated in the synapto-toxic effects of Aβ oligomers (8,49,50).…”