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

23/08/2026

AI Summary

Zonisamide markedly improved spatial learning, memory and alleviated psychiatric symptoms in 5xFAD Alzheimer's disease mouse model.
Zonisamide increased synaptic proteins PSD95, synaptophysin, BDNF and SAPAP3; SAPAP3 knockdown blocked ZNS regulation of PSD95 and NMDAR2A.
Zonisamide reduced Aβ deposition, downregulated APP, p-APP(Thr668), BACE1 and PS1, and attenuated tau Ser396 phosphorylation via ERK1/2 inhibition.

Eur J Pharmacol. 2026 Aug 22:179279. doi: 10.1016/j.ejphar.2026.179279. Online ahead of print.

ABSTRACT

BACKGROUND: Alzheimer’s disease (AD) is characterized by pathological changes in Aβ&Tau, 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.

AIM: We aims to investigate the therapeutic efficacy of ZNS for AD and its potential molecular mechanisms.

METHODS: 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.

RESULTS: 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.

CONCLUSION: 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 | DOI:10.1016/j.ejphar.2026.179279

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