Affiliations: [a] Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, P. R. China | [b] The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, P. R. China | [c] Jiangsu Key Laboratory for Molecular Medicine, Nanjing University, Nanjing, P. R. China | [d] Department of Neurology, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, P. R. China | [e] Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu, Nanjing Medical University, Nanjing, P. R. China
Correspondence:
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Correspondence to: Yun Xu and Hui Zhao MD, PhD, Department of Neurology, Drum Tower Hospital, Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu, 210008, P. R. China. Tel.: +86 25 68182212; Fax: +86 25 83105208; E-mails: [email protected] (Y. Xu) [email protected] (Hui Zhao).
Abstract: Amyloid-β (Aβ) is a key neuropathological hallmark of Alzheimer’s disease (AD). Postsynaptic density protein 93 (PSD-93) is a key scaffolding protein enriched at postsynaptic sites. The aim of the present study was to examine whether PSD-93 overexpression could alleviate Aβ-induced cognitive dysfunction in APPswe/PS1dE9 (APP/PS1) mice by reducing Aβ levels in the brain. The level of PSD-93 was significantly decreased in the hippocampus of 6-month-old APP/PS1 mice compared with that in wild-type mice. Following lentivirus-mediated PSD-93 overexpression, cognitive function, synaptic function, and amyloid burden were investigated. The open field test, Morris water maze test, and fear condition test revealed that PSD-93 overexpression ameliorated spatial memory deficits in APP/PS1 mice. The facilitation of long-term potentiation induction was observed in APP/PS1 mice after PSD-93 overexpression. The expression of somatostatin receptor 4 (SSTR4) and neprilysin was increased, while the amyloid plaque load and Aβ levels were decreased in the brains of APP/PS1 mice. Moreover, PSD-93 interacted with SSTR4 and affected the level of SSTR4 on cell membrane, which was associated with the ubiquitination. Together, these findings suggest that PSD-93 attenuates spatial memory deficits and decreases amyloid levels in APP/PS1 mice, which might be associated with Aβ catabolism, and overexpression of PSD-93 might be a potential therapy for AD.
Keywords: Alzheimer’s disease, amyloid-β, postsynaptic density protein 93, somatostatin receptor 4
