GPR55 deficiency exacerbates cognitive impairments and Alzheimer's disease-like pathology in mice

IF 5.5 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international Pub Date : 2026-01-01 Epub Date: 2025-12-15 DOI:10.1016/j.neuint.2025.106105

Bing Fan , YuSheng Liang , TianTian Zhi , Lei Wu , YangXia Wu , Yan Yang , Zhi Xie , Xian Wu

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引用次数: 0

Abstract

Background

Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive cognitive decline and neuronal damage. Although studies have indicated a link between G-protein coupled receptor 55 (GPR55) and AD-related cognitive impairment, the underlying mechanisms remain unclear. Here, we aim to further investigate the role of GPR55 in the pathogenesis of AD.

Methods

We used viral vectors to knock down GPR55 expression in the hippocampus of normal mice. We also generated GPR55 knockout in AD mice by crossing GPR55^−/− mice with APP/PS1 transgenic mice (APP/PS1; GPR55^−/−). Behavioral tests were conducted to assess spatial memory deficits in 9-month-old APP/PS1; GPR55^−/− mice. We also assessed the amyloid β (Aβ) deposition, glial cell activation, and synaptic protein expression in the hippocampus. In addition, we used AAV9 viruses to overexpress GPR55 in the hippocampus of APP/PS1; GPR55^−/− mice to further observe its effect on cognitive function.

Results

Knockdown of GPR55 in the hippocampus induces AD-like pathology, cognitive dysfunction, neuroinflammation, and synaptic plasticity damage in normal mice. This was evidenced by increased hippocampal levels of Aβ and p-Tau, enhanced glial cell activation accompanied by upregulation of proinflammatory cytokines, and aggravated synaptic plasticity damage in the normal mice. Furthermore, knockdown of GPR55 induced the reduction of P-AKT1/2/3/AKT1/2/3 and P-GSK3β/GSK3β, while increasing the expression of P-ERK1/2/ERK1/2 in the hippocampus of normal mice. In addition, GPR55 deficiency exacerbated AD-like pathology and spatial learning and memory deficits in APP/PS1 mice. Conversely, AAV9-mediated overexpression of GPR55 rescued spatial memory impairments in APP/PS1; GPR55^−/− mice.

Conclusions

These findings underscore the critical role of GPR55 in AD progression and highlight its potential as a therapeutic target for AD treatment.

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GPR55缺乏会加剧小鼠的认知障碍和阿尔茨海默病样病理。

背景：阿尔茨海默病（AD）是最常见的痴呆症类型，以进行性认知能力下降和神经元损伤为特征。虽然研究表明g蛋白偶联受体55 （GPR55）与ad相关的认知障碍之间存在联系，但其潜在机制尚不清楚。在此，我们旨在进一步研究GPR55在AD发病机制中的作用。方法：采用病毒载体敲低正常小鼠海马组织中GPR55的表达。我们还通过将GPR55-/-小鼠与APP/PS1转基因小鼠（APP/PS1; GPR55-/-）杂交，在AD小鼠中实现了GPR55基因敲除。应用行为测试评估9月龄APP/PS1患儿空间记忆缺陷；GPR55 - / -小鼠。我们还评估了海马中β淀粉样蛋白（Aβ）沉积、胶质细胞活化和突触蛋白表达。此外，我们利用AAV9病毒在APP/PS1海马区过表达GPR55；进一步观察GPR55-/-对小鼠认知功能的影响。结果：正常小鼠海马GPR55表达下调可引起ad样病理、认知功能障碍、神经炎症和突触可塑性损伤。正常小鼠海马Aβ和p-Tau水平升高，胶质细胞活化增强，伴促炎细胞因子上调，突触可塑性损伤加重，均证明了这一点。此外，GPR55的下调可导致正常小鼠海马组织中P-AKT1/2/3/AKT1/2/3和P-GSK3β/GSK3β的表达减少，而P-ERK1/2/ERK1/2的表达增加。此外，GPR55缺乏加重了APP/PS1小鼠ad样病理和空间学习记忆缺陷。相反，aav9介导的GPR55过表达可挽救APP/PS1的空间记忆障碍；GPR55 - / -小鼠。结论：这些发现强调了GPR55在AD进展中的关键作用，并强调了其作为AD治疗靶点的潜力。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurochemistry international 医学-神经科学

CiteScore

8.40

自引率

2.40%

发文量

128

审稿时长

37 days

期刊介绍： Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.