Reprogramming lipid metabolism for cognitive restoration in Alzheimer's via PLA2G4E

IF 7.4 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2026-07-05 DOI:10.1002/trc2.70285

Sara Badesso, María Espelosín, Cristina Alonso, Alejandro Montilla, Maria Collantes, Mar Cuadrado-Tejedor, Ana García-Osta

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引用次数: 0

Abstract

INTRODUCTION

Growing evidence implicates dysregulated brain lipid metabolism in Alzheimer's disease (AD) pathogenesis, influencing membrane integrity, neuroinflammation, and amyloid beta and tau pathology, thereby representing a promising therapeutic target. However, therapeutic strategies targeting lipid pathways remain largely unexplored.

METHODS

The therapeutic potential of PLA2G4E, previously identified in our earlier work, was validated in the APP^NL-G-F AD mouse model using a translational gene-delivery approach with a blood–brain barrier–penetrant adeno-associated vector (AAV) (AAVP31) to achieve widespread brain expression. Brain lipidomics was performed to investigate the molecular mechanisms underlying treatment effects.

RESULTS

PLA2G4E expression rescued memory deficits, reduced tau phosphorylation, and improved brain glucose metabolism and cognitive performance in AD models and aged wild-type mice. These effects were accompanied by partial normalization of disease-associated lipid metabolic alterations.

DISCUSSION

These findings support PLA2G4E as a promising therapeutic target in AD and provide mechanistic evidence linking modulation of lipid metabolic pathways to synaptic and cognitive rescue.

Abstract Image

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通过PLA2G4E重编程脂质代谢促进阿尔茨海默病认知恢复。

越来越多的证据表明，脑脂质代谢失调在阿尔茨海默病（AD）的发病机制中，影响膜完整性，神经炎症，淀粉样蛋白和tau蛋白病理，因此代表了一个有希望的治疗靶点。然而，针对脂质途径的治疗策略在很大程度上仍未被探索。方法：在我们之前的工作中发现的PLA2G4E的治疗潜力，在APPNL-G-F AD小鼠模型中得到验证，使用翻译基因传递方法与血脑屏障渗透腺相关载体（AAV）（AAVP31）一起实现广泛的脑表达。脑脂质组学研究治疗效果的分子机制。结果：PLA2G4E的表达改善了AD模型和老年野生型小鼠的记忆缺陷，降低了tau磷酸化，改善了脑葡萄糖代谢和认知能力。这些影响伴随着与疾病相关的脂质代谢改变的部分正常化。讨论：这些发现支持PLA2G4E作为一种有希望的AD治疗靶点，并提供了将脂质代谢途径调节与突触和认知恢复联系起来的机制证据。

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

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.