Dl-3-n-Butylphthalide Reduces Cognitive Deficits and Alleviates Neuropathology in P301S Tau Transgenic Mice.

Yanmin Chang,Xingjun Jiang,Lulu Li,Rong Ma,Yanqing Wu,Junjie Hu,Zemin Wang,Gang Li,Yi Yao

doi:10.3389/fnins.2021.620176

Abstract

Alzheimer’s disease (AD) is a destructive and burdensome neurodegenerative disease, one of the most common characteristics of which are neurofibrillary tangles (NFTs) that are composed of abnormal tau protein. Animal studies have suggested that dl-3-n-butylphthalide (dl-NBP) alleviates cognitive impairment in mouse models of APP/PS1 and SAMP8. However, the underlying mechanisms related to this remain unclear. In this study, we examined the effects of dl-NBP on learning and memory in P301S transgenic mice, which carry the human tau gene with the P301S mutation. We found that dl-NBP supplementation effectively improved behavioral deficits and rescued synaptic loss in P301S tau transgenic mice, compared with vehicle-treated P301S mice. Furthermore, we also found that it markedly inhibited the hyperphosphorylated tau at the Ser262 site and decreased the activity of MARK4, which was associated with tau at the Ser262 site. Finally, dl-NBP treatment exerted anti-inflammatory effects and reduced inflammatory responses in P301S mice. In conclusion, our results provide evidence that dl-NBP has a promising potential for the therapy of tauopathies, including AD.

Highlights

Alzheimer’s disease (AD), the foremost cause of dementia in the elderly, is a complex multi-factorial neurodegenerative disease
We found that the administration of dl-NBP significantly decreased the levels of hyperphosphorylated tau at Ser262 in P301S mice, compared with vehicle-controlled mice
As GSK3β, CDK5, Phosphatase 2A (PP2A), and MARK4 have been linked to tau hyperphosphorylation, we explored the expression of these kinases and phosphatases after treatment with dl-NBP

Summary

Introduction

Alzheimer’s disease (AD), the foremost cause of dementia in the elderly, is a complex multi-factorial neurodegenerative disease. NFTs are formed by the aggregation of paired helical filaments (PHFs) composed of truncated and hyperphosphorylated microtubule-associated protein tau (Arai et al, 1990; Braak and Braak, 1991; Citron, 2010). The latter type of lesion characterizes a variety of human neurodegenerative diseases collectively termed “tauopathies” (Murray et al, 2014; Kovacs, 2015), including AD, progressive supranuclear palsy, corticobasal degeneration, and Pick’s disease (Spillantini and Goedert, 2013; Wang and Mandelkow, 2016). P301S is a mouse model that overexpresses the human tau gene with the P301S mutation in exon 10

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