Loss of lysosomal acid lipase contributes to Alzheimer's disease pathology and cognitive decline.

ABSTRACT:

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 indic

SUBMITTER: Barnett AM 

PROVIDER: S-EPMC12271982 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature