Amyloid-β-Induced Dysregulation of AMPA Receptor Trafficking.

Sumasri Guntupalli,Jocelyn Widagdo,Victor Anggono

doi:10.1155/2016/3204519

Abstract

Evidence from neuropathological, genetic, animal model, and biochemical studies has indicated that the accumulation of amyloid-beta (Aβ) is associated with, and probably induces, profound neuronal changes in brain regions critical for memory and cognition in the development of Alzheimer's disease (AD). There is considerable evidence that synapses are particularly vulnerable to AD, establishing synaptic dysfunction as one of the earliest events in pathogenesis, prior to neuronal loss. It is clear that excessive Aβ levels can disrupt excitatory synaptic transmission and plasticity, mainly due to dysregulation of the AMPA and NMDA glutamate receptors in the brain. Importantly, AMPA receptors are the principal glutamate receptors that mediate fast excitatory neurotransmission. This is essential for synaptic plasticity, a cellular correlate of learning and memory, which are the cognitive functions that are most disrupted in AD. Here we review recent advances in the field and provide insights into the molecular mechanisms that underlie Aβ-induced dysfunction of AMPA receptor trafficking. This review focuses primarily on NMDA receptor- and metabotropic glutamate receptor-mediated signaling. In particular, we highlight several mechanisms that underlie synaptic long-term depression as common signaling pathways that are hijacked by the neurotoxic effects of Aβ.

Highlights

Alzheimer’s disease (AD) is the most common cause of dementia among the aging population
NMDA receptors (NMDARs)-dependent long-term potentiation (LTP) and long-term depression (LTD) are two major forms of synaptic plasticity that are best studied in the hippocampus, a region of the brain that is both critical for memory formation and highly vulnerable to Aβ toxicity
Recent studies have shown that NMDAR-induced glycogen synthase kinase-3β (GSK3β) phosphorylation of tau at Ser-396 is required for hippocampal LTD by enhancing the interaction between the GluA2 subunits of AMPA receptors (AMPARs) with the protein interacting with C-kinase 1 (PICK1) [69, 70], a process that is fundamental for AMPAR internalization and/or intracellular retention during LTD [71,72,73,74,75,76]

Summary

Introduction

Alzheimer’s disease (AD) is the most common cause of dementia among the aging population. Recent studies have shown that soluble oligomeric forms of Aβ (ranging from dimers and trimers to dodecamers) exert potent and acute neurotoxic effects on the structure and function of synapses, including reduced excitatory synaptic transmission, loss of dendritic spines, and aberrant neuronal network activity [4, 5]. These deleterious effects could contribute to the cognitive deficit and memory loss associated with AD, indicating that “synaptic failure” is likely to be one of the earliest events that occurs in the pathogenesis of AD prior to neuronal loss [6,7,8]. Several pharmacological agents that target these pathways and are efficacious in inhibiting or reversing the neurotoxic effects of Aβ on glutamatergic neurotransmission and synaptic plasticity are discussed

Aβ Alters Synaptic Plasticity In Vitro and In Vivo

Mechanisms Underlying Aβ-Induced Deficits in AMPAR Function

Concluding Remarks