Amyloid-β Induces Caspase-Dependent Loss of PSD-95 and Synaptophysin Through NMDA Receptors

摘要: Soluble oligomeric amyloid-β (Aβ) is thought to induce synaptic dysfunction during early stages of Alzheimer's disease (AD). In this report, we show that soluble Aβ downregulates the levels two proteins, PSD-95 and synaptophysin, effect can be blocked by MK-801 (NMDAR antagonist) ifenprodil (NR2B antagonist). Low (1 μM) high (10 doses NMDA, respectively, prevented potentiated actions Aβ. Blockade NR2A or NMDAR eliminated protective 1 μM while effects 10 NMDA were only abolished ifenprodil. Caspase-8, acting upstream caspase-3, was found mediate synaptotoxic in an ifenprodil-reversible fashion. Thus, leads a loss proteins suppression function activation NR2B subsequent induction caspase-8 caspase-3 activities. The identified novel mechanism through which initiates suggests selective enhancement activity and/or reduction halt manifestation key early-stage event AD.