Title : C-terminal domains of GluA2 regulate amyloid-beta induced synaptic and cognitive impairments
Abstract:
Objective: Synaptic dysfunction is one of the early symptoms of AD, which occurs much earlier than the formation of amyloid plaques and neurofibrillary tangles. Synaptic function is closely related to the number and synaptic localization of AMPA receptors (AMPARs), and this process is directly regulated by the interaction of AMPAR carboxy-terminal domains (CTDs) and their intracellular proteins. It has been found that changes in AMPAR number and synaptic localization occur in the early stages of AD, but it is still unknown whether AMPAR-CTDs are directly involved in regulating synaptic dysfunction in early AD and whether interfering with the interaction of AMPARs and intracellular proteins can rescue synaptic and cognitive dysfunction.
Methods: In this study, we applied A2C1KI mice, which have the intracellular domain of GluA2 replaced with that of GluA1 (altering the interaction between AMPAR and intracellular proteins), and treated them with amyloid-beta oligomers (Aβo), or crossed them with AD4T transgenic mice that overproduced Aβ to generate double hybrid mice. We also designed differently interfering peptides and viruses to find the key sites of CTDs further and intervene in the interaction of AMPARs with intracellular proteins. Electrophysiological and behavior tests were used to explore the synaptic function and cognitive function of different treatment groups.
Results: Aβo did not impair synaptic function and cognitive impairment in A2C1KI mice, and when we further interfered with the interaction between GluA2 and different intracellular proteins in WT mice, the toxic effects of Aβ oligomers on the central nervous system could be blocked. In AD4T mice with A2C1KI or interference peptide, synaptic function, and cognitive performance were greatly improved. Conclusion This study reveals that the GluA2-CTDs and its intracellular proteins play an important role in early synaptic damage and cognitive impairments in AD, and interfering with its interaction can significantly rescue AD-like performance at different levels.
Audience Take Away
- This research presents kinds of valuable methods to model early Alzheimer's disease with synaptic failure
- This research originally explains the role and mechanism of specific domains of key synaptic molecules in the pathogenesis of Alzheimer's disease
- This research introduces an effective intervention in the prevention and treatment of early Alzheimer's disease
