Reduced PIN1 expression in neocortical and limbic brain regions in female Alzheimer’s patients correlates with cognitive and neuropathological phenotypes

IF 3.7 3区医学 Q2 GERIATRICS & GERONTOLOGY

Neurobiology of Aging Pub Date : 2024-06-29 DOI:10.1016/j.neurobiolaging.2024.06.007

Camila de Ávila , Crystal Suazo , Jennifer Nolz , J. Nicholas Cochran , Qi Wang , Ramon Velazquez , Eric Dammer , Benjamin Readhead , Diego Mastroeni

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引用次数: 0

Abstract

Women have a higher incidence of Alzheimer’s disease (AD), even after adjusting for increased longevity. Thus, there is an urgent need to identify genes that underpin sex-associated risk of AD. PIN1 is a key regulator of the tau phosphorylation signaling pathway; however, potential differences in PIN1 expression, in males and females, are still unknown. We analyzed brain transcriptomic datasets focusing on sex differences in PIN1 mRNA levels in an aging and AD cohort, which revealed reduced PIN1 levels primarily within females. We validated this observation in an independent dataset (ROS/MAP), which also revealed that PIN1 is negatively correlated with multiregional neurofibrillary tangle density and global cognitive function in females only. Additional analysis revealed a decrease in PIN1 in subjects with mild cognitive impairment (MCI) compared with aged individuals, again driven predominantly by female subjects. Histochemical analysis of PIN1 in AD and control male and female neocortex revealed an overall decrease in axonal PIN1 protein levels in females. These findings emphasize the importance of considering sex differences in AD research.

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女性阿尔茨海默氏症患者新皮质和边缘脑区 PIN1 表达的减少与认知和神经病理学表型相关。

即使考虑到寿命的延长，女性阿尔茨海默病（AD）的发病率也更高。因此，我们迫切需要找出与性别相关的阿尔茨海默病风险基因。PIN1 是 tau 磷酸化信号通路的一个关键调节因子；然而，PIN1 在男性和女性中的潜在表达差异仍然未知。我们分析了大脑转录组数据集，重点研究了老年痴呆症队列中 PIN1 mRNA 水平的性别差异。我们在一个独立的数据集（ROS/MAP）中验证了这一观察结果，该数据集还显示，PIN1 与多区域神经纤维缠结密度和女性的整体认知功能呈负相关。其他分析表明，与老年患者相比，轻度认知障碍（MCI）患者的 PIN1 有所下降，同样主要是女性患者。对AD和对照组男性和女性新皮质中PIN1的组织化学分析显示，女性轴突PIN1蛋白水平总体下降。这些发现强调了在注意力缺失症研究中考虑性别差异的重要性。

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

Neurobiology of Aging 医学-老年医学

CiteScore

8.40

自引率

2.40%

发文量

225

审稿时长

67 days

期刊介绍： Neurobiology of Aging publishes the results of studies in behavior, biochemistry, cell biology, endocrinology, molecular biology, morphology, neurology, neuropathology, pharmacology, physiology and protein chemistry in which the primary emphasis involves mechanisms of nervous system changes with age or diseases associated with age. Reviews and primary research articles are included, occasionally accompanied by open peer commentary. Letters to the Editor and brief communications are also acceptable. Brief reports of highly time-sensitive material are usually treated as rapid communications in which case editorial review is completed within six weeks and publication scheduled for the next available issue.