Pigment Epithelium‐Derived Factor Deficiency Impairs Hippocampal Glutamate Homeostasis and Cognitive Function by Downregulating Astrocytic GLT‐1

Maintenance of glutamate homeostasis is essential for synaptic plasticity and cognition. Disrupted glutamate-glutamine cycling causes chronic excitotoxicity, a key driver of cognitive deficits in Alzheimer's disease (AD), though regulatory mechanisms remain unclear. Pigment epithelium-derived factor (PEDF), a neuroprotective protein declining with age, is demonstrated here to play a novel role in synaptic glutamate clearance. Analysis of peripheral blood samples from 19 patients with AD and 75 non-dementia control subjects revealed lower levels of PEDF in patients, and loss of PEDF correlates with cognitive decline. PEDF-deficient mice exhibit defective learning and memory, and higher susceptibility to AD. Furthermore, PEDF deficiency impaired synaptic plasticity and dendritic spine morphology. Mechanistically, PEDF inhibits ubiquitin-proteasome-dependent degradation of astrocytic glutamate transporter-1 (GLT-1) and normally guarantees elimination of synaptic glutamate by modulating the protein kinase C signaling pathway. Strikingly, restoring PEDF rescued cognitive deficits in a mouse model of AD, and upregulation of GLT-1 rescued cognitive impairment in PEDF-deficient mice. Collectively, these findings reveal PEDF is a physiologic regulator of synaptic glutamate homeostasis. Targeting PEDF deficiency-induced neural impairment may provide a novel avenue for the development of new therapeutic applications for neurodegenerative diseases associated with glutamate-induced excitotoxicity.