Barnett Alexandra M, McNair Elizabeth M, Dawkins Lamar, Zou Jian, Nikolova Viktoriya D, Moy Sheryl S, Sutherland Greg T, Stevens Julia, Colie Meagan, Katemboh Kemi, Kellner Hope, Ho Katherine, Damian Corina, DeCastro Sagan, Vetreno Ryan P, Coleman Leon G
Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
Alzheimers Dement. 2025 Jul;21(7):e70486. doi: 10.1002/alz.70486.
Underlying drivers of Alzheimer's disease (AD) remain unknown, though several distinct risk exposures share a common pathological progression.
The cellular and molecular consequences of two common midlife AD risk factors-heavy alcohol use and obesity-were compared to uncover novel mediators that contribute to AD.
Both AD risk exposures reduced levels of neuronal lysosomal acid lipase (LAL), which contributed to AD pathology and cognitive decline. LAL was lost with age in mice and humans with greater losses in AD and inverse associations with amyloid β (Aβ). LAL loss preceded Aβ pathology in AD mice, and neuronal LAL knockdown enhanced pathology and cognitive decline. In human AD brain, robust reductions in LAL protein were found with indications of a transcriptional mechanism. LAL gene therapy reduced pathology and improved cognition and affect in vivo.
LAL loss is an age-related contributor to AD pathology that can be targeted therapeutically.
The loss of lysosomal acid lipase (LAL) contributes to Alzheimer's disease progression. LAL is lost is normal aging and Alzheimer's disease risk exposures. LAL loss is greater in human Alzheimer's brain and predicts the extent of pathology. LAL gene therapy blunts Alzheimer' pathology, improving cognition and mood with age.
尽管几种不同的风险因素有着共同的病理进展过程，但阿尔茨海默病（AD）的潜在驱动因素仍不明确。
比较了两种常见的中年AD风险因素——大量饮酒和肥胖——在细胞和分子层面的影响，以发现导致AD的新介质。
两种AD风险因素均降低了神经元溶酶体酸性脂肪酶（LAL）的水平，这导致了AD病理变化和认知能力下降。在小鼠和人类中，LAL水平会随着年龄增长而降低，在AD患者中下降更为明显，且与β淀粉样蛋白（Aβ）呈负相关。在AD小鼠中，LAL水平下降先于Aβ病理变化出现，而神经元LAL基因敲低会加剧病理变化和认知能力下降。在人类AD大脑中，发现LAL蛋白显著减少，提示存在转录机制。LAL基因治疗可减轻病理变化，改善体内认知和情感状态。
LAL水平下降是AD病理变化中与年龄相关的一个因素，可作为治疗靶点。
溶酶体酸性脂肪酶（LAL）水平下降会导致阿尔茨海默病进展。LAL水平在正常衰老和AD风险因素作用下都会下降。在人类AD大脑中LAL水平下降更为明显，并可预测病理变化程度。LAL基因治疗可减轻阿尔茨海默病病理变化，随着年龄增长改善认知和情绪。
