Sex-specific modulation of FOLR1 and its cycle enzyme genes in Alzheimer's disease brain regions.

IF 3.2 3区医学 Q2 ENDOCRINOLOGY & METABOLISM

Metabolic brain disease Pub Date : 2025-03-28 DOI:10.1007/s11011-025-01578-x

Cristina Sanfilippo, Paola Castrogiovanni, Rosa Imbesi, Michele Vecchio, Manlio Vinciguerra, Kaj Blennow, Henrik Zetterberg, Michelino Di Rosa

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引用次数: 0

Abstract

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive and functional decline. Its incidence increases significantly with age and is more prevalent in women than men. We investigated the folate receptor alpha (FOLR1) gene expression levels in the central nervous system (CNS) of AD and non-demented healthy control (NDHC) subjects. Our cohort included 3,946 samples: 2,391 NDHC and 1,555 AD patients, stratified by brain region, age, and sex. Interestingly, a significant increase in FOLR1 expression was observed only in females with AD compared to NDHC females. Furthermore, we found that FOLR1 expression was differentially increased in the prefrontal cortex (PFC) and diencephalon (DIE) only in AD females. Moreover, in females, genes involved in the folic acid (FA) cycle that drives DNA synthesis were significantly modulated. In contrast, in males, downregulation of TYMS effectively blocks the completion of the cycle, thereby preventing downstream DNA synthesis. Tissue Transcriptome Deconvolution (TTD) analysis revealed astrocytes and endothelial cells associated with FOLR1 expression in both AD males and females. Gene Ontology analysis supported these findings, showing enrichment in processes aligned with these cell types. Positive correlations between brain FOLR1 expression and markers for astrocytes (glial fibrillary acidic protein) and endothelial cells (CD31) provided further validation. Our findings suggest a potential role for sex-dependent FOLR1 expression and its association with specific brain regions and cellular processes in AD.

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阿尔茨海默病（AD）是最常见的痴呆症，其特点是认知能力和功能进行性下降。其发病率随着年龄的增长而明显增加，女性发病率高于男性。我们研究了AD和非痴呆健康对照组（NDHC）受试者中枢神经系统（CNS）中叶酸受体α（FOLR1）基因的表达水平。我们的队列包括3946个样本：我们的队列包括 3,946 份样本：2,391 份 NDHC 样本和 1,555 份 AD 患者样本，并按大脑区域、年龄和性别进行了分层。有趣的是，与 NDHC 女性患者相比，仅在 AD 女性患者中观察到 FOLR1 表达的显著增加。此外，我们还发现，FOLR1的表达仅在AD女性患者的前额叶皮层（PFC）和间脑（DIE）中有不同程度的增加。此外，在女性中，参与叶酸（FA）循环以驱动DNA合成的基因也受到了显著调控。相反，在男性中，TYMS的下调有效地阻止了叶酸循环的完成，从而阻止了下游DNA的合成。组织转录组解卷积（TTD）分析显示，在AD男性和女性中，星形胶质细胞和内皮细胞都与FOLR1的表达有关。基因本体分析支持了这些发现，显示了与这些细胞类型相一致的过程的富集。大脑FOLR1的表达与星形胶质细胞（胶质纤维酸性蛋白）和内皮细胞（CD31）的标记物之间的正相关进一步证实了这一点。我们的研究结果表明，性别依赖性 FOLR1 的表达及其与特定脑区和细胞过程的关联在注意力缺失症中具有潜在的作用。

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

Metabolic brain disease 医学-内分泌学与代谢

CiteScore

5.90

自引率

5.60%

发文量

248

审稿时长

6-12 weeks

期刊介绍： Metabolic Brain Disease serves as a forum for the publication of outstanding basic and clinical papers on all metabolic brain disease, including both human and animal studies. The journal publishes papers on the fundamental pathogenesis of these disorders and on related experimental and clinical techniques and methodologies. Metabolic Brain Disease is directed to physicians, neuroscientists, internists, psychiatrists, neurologists, pathologists, and others involved in the research and treatment of a broad range of metabolic brain disorders.