Loss of neuronal lysosomal acid lipase drives amyloid pathology in Alzheimer's disease.
| Autor: | Barnett AM; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC.; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC., Dawkins L; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC.; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC., Zou J; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC.; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC., McNair E; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC.; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC., Nikolova VD; University of North Carolina at Chapel Hill School of Medicine, Department of Psychiatry, Chapel Hill, NC.; University of North Carolina at Chapel Hill, Carolina Institute for Developmental Disabilities, Chapel Hill, NC., Moy SS; University of North Carolina at Chapel Hill School of Medicine, Department of Psychiatry, Chapel Hill, NC.; University of North Carolina at Chapel Hill, Carolina Institute for Developmental Disabilities, Chapel Hill, NC., Sutherland GT; New South Wales Brain Tissue Resource Centre and Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdon, Australia., Stevens J; New South Wales Brain Tissue Resource Centre and Charles Perkins Centre, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Camperdon, Australia., Colie M; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC., Katemboh K; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC., Kellner H; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC., Damian C; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC., DeCastro S; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC.; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC., Vetreno RP; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC.; University of North Carolina at Chapel Hill School of Medicine, Department of Psychiatry, Chapel Hill, NC., Coleman LG Jr; University of North Carolina at Chapel Hill School of Medicine, Department of Pharmacology, Chapel Hill, NC.; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC. |
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| Jazyk: | angličtina |
| Zdroj: | BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 10. Date of Electronic Publication: 2024 Jun 10. |
| DOI: | 10.1101/2024.06.09.596693 |
| Abstrakt: | Underlying drivers of late-onset Alzheimer's disease (LOAD) pathology remain unknown. However, multiple biologically diverse risk factors share a common pathological progression. To identify convergent molecular abnormalities that drive LOAD pathogenesis we compared two common midlife risk factors for LOAD, heavy alcohol use and obesity. This revealed that disrupted lipophagy is an underlying cause of LOAD pathogenesis. Both exposures reduced lysosomal flux, with a loss of neuronal lysosomal acid lipase (LAL). This resulted in neuronal lysosomal lipid (NLL) accumulation, which opposed Aβ localization to lysosomes. Neuronal LAL loss both preceded (with aging) and promoted (targeted knockdown) Aβ pathology and cognitive deficits in AD mice. The addition of recombinant LAL ex vivo and neuronal LAL overexpression in vivo prevented amyloid increases and improved cognition. In WT mice, neuronal LAL declined with aging and correlated negatively with entorhinal Aβ. In healthy human brain, LAL also declined with age, suggesting this contributes to the age-related vulnerability for AD. In human LOAD LAL was further reduced, correlated negatively with Aβ Competing Interests: Competing interests: The first and senior author are inventors on patent 5470.946.WO entitled: Targeting lysosomal lipid in Alzheimer’s disease. The first and senior author are inventors on patent 5470.946PR entitled: Targeting lysosomal lipid in Alzheimer’s disease. |
| Databáze: | MEDLINE |
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