Approximately 5 million Americans currently suffer from Alzheimer's disease (AD) a neurodegenerative disorder characterized by progressive impairment of cognitive function and emotional and sleep disturbances. This laboratory has developed cell culture and mouse models of AD, and have used these models to elucidate the biochemical and molecular events responsible for neuronal dysfunction and death in AD. We have found that there are abnormalities in lipid metabolism in the brains of patients with AD. Specifically, levels of cholesterol and long-chain ceramides are increased. Studies of experimental animal and cell culture models of AD suggest that increased oxidative stress, associated with amyloid deposition is responsible for the lipid abnormalities. Antioxidants and drugs that prevent the production of ceramides protect neurons from being damaged and killed by amyloid suggesting an important role for the lipid abnormalities in the disease process. Membrane lipid peroxidation appears to play an important role in amyloidogenic processing of the amyloid precursor protein as the lipid peroxidation product 4-hydroxynonenal covalently modifies the protein nicastrin and thereby increases gamma-secretase activity. In other studies we have identified a novel protein called Herp (homocysteine responsive endoplasmic reticulum protein) that can protect neurons from being damaged and killed by amyloid and a presenilin mutation. In addition, we have found that dietary restriction can reduce amyloid deposition and protect neurons from being damaged and killed in animal models of AD, and that this beneficial effect of dietary restriction involves stimulation of the production of brain-derived neurotrophic factor (BDNF). Antidepressant serotonin reuptake inhibitors can reduce amyloid deposition and improve cognitive function in a mouse model of AD, suggesting a potential prophylactic/therapeutic use of such drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000312-05
Application #
7132237
Study Section
(LNS)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Mattson, Mark P; Arumugam, Thiruma V (2018) Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab 27:1176-1199
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Okun, Eitan; Mattson, Mark P; Arumugam, Thiruma V (2010) Involvement of Fc receptors in disorders of the central nervous system. Neuromolecular Med 12:164-78
Hutchison, Emmette R; Okun, Eitan; Mattson, Mark P (2009) The therapeutic potential of microRNAs in nervous system damage, degeneration, and repair. Neuromolecular Med 11:153-61
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Mattson, Mark P; Wan, Ruiqian (2008) Neurotrophic factors in autonomic nervous system plasticity and dysfunction. Neuromolecular Med 10:157-68
Harel, Asaff; Wu, Fangbai; Mattson, Mark P et al. (2008) Evidence for CALM in directing VAMP2 trafficking. Traffic 9:417-29
Kim, So Jung; Son, Tae Gen; Park, Hee Ra et al. (2008) Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem 283:14497-505
Nelson, Rhonda L; Guo, Zhihong; Halagappa, Veerendra Madala et al. (2007) Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice. Exp Neurol 205:166-76

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