Journal
COMMUNICATIONS BIOLOGY
Volume 5, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-022-04011-6
Keywords
-
Categories
Funding
- Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health) [U01 AG024904]
- DOD ADNI (Department of Defense) [W81XWH-12-2-0012]
- National Institute on Aging
- National Institute of Biomedical Imaging and Bioengineering
- AbbVie
- Alzheimer's Association
- Alzheimer's Drug Discovery Foundation
- Araclon Biotech
- BioClinica, Inc.
- Biogen
- CereSpir, Inc.
- Cogstate
- Eisai Inc.
- Elan Pharmaceuticals, Inc.
- Eli Lilly and Company
- EuroImmun
- F. Hoffmann-La Roche Ltd.
- Fujirebio
- GE Healthcare
- IXICO Ltd.
- Janssen Alzheimer Immunotherapy Research & Development, LLC
- Johnson & Johnson Pharmaceutical Research & Development LLC
- Lumosity
- Lundbeck
- Merck Co., Inc.
- Meso Scale Diagnostics, LLC
- NeuroRx Research
- Neurotrack Technologies
- Novartis Pharmaceuticals Corporation
- Pfizer Inc.
- Piramal Imaging
- Servier
- Takeda Pharmaceutical Company
- Transition Therapeutics
- Canadian Institutes of Health Research
- National Institute on Aging [P30AG10161, R01AG15819, R01AG17917, U01AG46152, U01AG61356]
- National Institute on Aging (NIA) [R01 AG059093]
- NIA's national initiatives AMP-AD and M2OVE-AD [R01 AG046171, RF1 AG051550, 3U01 AG061359-02S1, 3U01 AG024904-09S4]
- NIA [RF1 AG058942, R01 AG057452, R01 AG069901, RF1 AG061872, 5U01 AG061359-02, 5U01 AG061359-03, R01AG062514, U01AG046139, R03 AG054936]
- Qatar National Research Fund [NPRP8-061-3-011]
- NIH [NLM R01 LM012535, NIA R03 AG054936, P30 AG010133, P30 AG072976, R01 AG019771, R01 AG057739, U19 AG024904, R01 LM013463, R01 AG068193, T32 AG071444, U01 AG068057, U01 AG072177]
- Bristol-Myers Squibb Company
- Genentech, Inc.
Ask authors/readers for more resources
This study investigates the role of sphingomyelin and ceramide metabolism in Alzheimer's disease through multi-omics analyses and imaging features. The findings suggest potential therapeutic targets in the sphingomyelin pathway and demonstrate the efficacy of modulators of S1P metabolism in treating Alzheimer's disease, as validated in mouse models.
Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment. Complementary multi-omics approach, in silico metabolic flux, and neuroimaging analyses link the sphingolipid pathway to Alzheimer's disease pathogenesis with therapeutic targets validated using behavioral assessments in amyloidogenic APP/PS1 mice.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available