Knockdown of astrocytic Grin2a aggravates β-amyloid-induced memory and cognitive deficits through regulating nerve growth factor

Synapse degeneration correlates strongly with cognitive impairments in Alzheimer's disease (AD) patients. Soluble Amyloid-beta (A beta) oligomers are thought as the major trigger of synaptic malfunctions. Our earlier studies have demonstrated that A beta oligomers interfere with synaptic function through N-methyl-D-aspartate receptors (NMDARs). Our recent in vitro study found the neuroprotective role of astrocytic GluN2A in the promotion of synapse survival and identified nerve growth factor (NGF) derived from astrocytes, as a likely mediator of astrocytic GluN2A buffering against A beta synaptotoxicity. Our present in vivo study focused on exploring the precise mechanism of astrocytic GluN2A influencing A beta synaptotoxicity through regulating NGF. We generated an adeno-associated virus (AAV) expressing an astrocytic promoter (GfaABC1D) shRNA targeted to Grin2a (the gene encoding GluN2A) to perform astrocyte-specific Grin2a knockdown in the hippocampal dentate gyrus, after 3 weeks of virus vector expression, A beta were bilaterally injected into the intracerebral ventricle. Our results showed that astrocyte-specific knockdown of Grin2a and A beta application both significantly impaired spatial memory and cognition, which associated with the reduced synaptic proteins PSD95, synaptophysin and compensatory increased NGF. The reduced astrocytic GluN2A can counteract A beta-induced compensatory protective increase of NGF through regulating pNF-kappa B, Furin and VAMP3, which modulating the synthesis, mature and secretion of NGF respectively. Our present data reveal, for the first time, a novel mechanism of astrocytic GluN2A in exerting protective effects on synapses at the early stage of A beta exposure, which may contribute to establish new targets for AD prevention and early therapy.