Zonisamide Improves Cognitive Impairment and Psychiatric Symptoms related with SAPAP3 in Mouse Models of Alzheimer's Disease.

Authors

Fangtai Yi, Jianfeng Ma, Ruiyue Zhao, Qiuyu Xie, Sitong Lu, Kailong Zhang, Zuodong Zhong, Huijuan OuYang, Yuan Qin, Mingheng Xu, Qin Xue, Xinlu Wang, Wei Wei, Yinghua Liu

Published in

European journal of pharmacology. Pages 179279. Aug 22, 2026. Epub Aug 22, 2026.

Abstract

Alzheimer's disease (AD) is characterized by pathological changes in AβΤ, cognitive impairment, and may also manifest psychiatric symptoms. Zonisamide (ZNS) has been demonstrated its improvement of cognitive dysfunction in T2DM mice in our previous study. However, the efficacy and mechanism of ZNS in treating AD remain unclear.
We aims to investigate the therapeutic efficacy of ZNS for AD and its potential molecular mechanisms.
Three-month-old 5xFAD mice were treated with ZNS (20 mg/kg, i.p.) for 12-week. The behavioral test assesses cognitive function and psychiatric symptoms. Aβ-PET/CT, immunofluorescence, and Thioflavine-S stainin staining assessed the levels of Aβ plaques. Proteomics and Western blot analyses evaluated synapse-associated proteins, amyloid precursor protein (APP) related proteins and phosphorylated tau.
We discovered for the first time that ZNS significantly improved spatial learning and memory, and also alleviated psychiatric symptoms in 5xFAD. Besides, ZNS increased PSD95, SYP, BDNF, and SAP90/PSD-95-related protein 3 (SAPAP3), which plays a crucial role in compulsive-like behaviors. Importantly, siRNA-mediated knockdown of SAPAP3 in N2A/APP cells inhibited the regulatory effect of ZNS on PSD95 and NMDAR2A (NR2A). In addition, ZNS treatment reduced Aβ deposition in the brain. It also downregulated APP, p-APP (Thr668), BACE1, and PS1, and attenuated tau phosphorylation at Ser396 by inhibiting its upstream kinase ERK1/2 activity.
ZNS exerts neuroprotective effects in 5xFAD mice and improves AD-related cognitive impairment and AD-like lesions, which establishes ZNS as a promising therapeutic avenue for AD and its associated psychiatric symptoms.

PMID:
42632510
Bibliographic data and abstract were imported from PubMed on 23 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.