2. Academic Validation
  3. Pigment Epithelium-Derived Factor Deficiency Impairs Hippocampal Glutamate Homeostasis and Cognitive Function by Downregulating Astrocytic GLT-1

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

  • Adv Sci (Weinh). 2025 Sep 14:e00402. doi: 10.1002/advs.202500402.
Jin-Hui Shi 1 2 3,  Qi-Long Tang 1,  Jin-Hong Wang 1,  Yan-Lan Long 1,  Sai-Feng Zhao 4 5,  Zhen Zhao 1,  Wan-Ting Xie 1,  Zi-Ming Li 4,  Hao-Ming Lu 1,  Tian-Xiao Gao 6,  Zhen-Zhen Fang 1,  Ti Zhou 1,  Bo-Xing Li 4 5,  Xia Yang 1,  Guo-Quan Gao 1 4 7 8,  Wei-Wei Qi 1 4 9
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
  • 2 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
  • 3 Department of Neurology, Chaozhou People's Hospital, Chaozhou, 521011, China.
  • 4 Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China.
  • 5 Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510655, China.
  • 6 Department of Nuclear Medicine, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
  • 7 Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, Guangdong, 510630, China.
  • 8 China Key Laboratory of Tropical Disease Control (Sun Yat-Sen University), Ministry of Education, Guangzhou, 510080, China.
  • 9 Guangdong Engineering & Technology Research Center for Gene Manipulation and Biomacromolecular Products (Sun Yat-sen University), Guangzhou, 510080, China.
PMID: 40946177 DOI: 10.1002/advs.202500402
Abstract

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.

Keywords

alzheimer's disease (AD); glutamate homeostasis; glutamate transporter‐1 (GLT‐1); pigment epithelium‐derived factor (PEDF).

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