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Updated: Sep 15, 2025

Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Loss of lysosomal acid lipase contributes to Alzheimer's disease pathology and cognitive decline
Alexandra M Barnett1,2, Elizabeth M McNair1,2, Lamar Dawkins1,2
1Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
Introduction:
Underlying drivers of Alzheimer's disease (AD) remain unknown, though several distinct risk exposures share a common pathological progression.
Methods:
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.
Results:
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.
Discussion:
LAL loss is an age-related contributor to AD pathology that can be targeted therapeutically.
Highlights:
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.
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