Approximately 5 million Americans currently suffer from Alzheimers 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. Additional findings suggest that there is a defect in DNA base excision repair in brain cells of AD patients and subjects with amnestic mild cognitive impairment. Moreover, 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. We have shown that diabetes causes a deficit in cognitive function which is associated with impaired hippocampal synaptic plasticity and neurogenesis;exercise and dietary energy restriction can counteract these adverse effects of diabetes. We recently demonstrated a therapeutic benefit of drugs used to improve glycemic control in animal models of diabetes and Alzheimer's disease, and we are moving forward with a clinical trial of one of these drugs, Exenatide, in human subjects with mild cognitive impairment or early stage Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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National Institute on Aging
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Zhang, Shi; Eitan, Erez; Wu, Tsung-Yu et al. (2018) Intercellular transfer of pathogenic ?-synuclein by extracellular vesicles is induced by the lipid peroxidation product 4-hydroxynonenal. Neurobiol Aging 61:52-65
Connolly, Niamh M C; Theurey, Pierre; Adam-Vizi, Vera et al. (2018) Guidelines on experimental methods to assess mitochondrial dysfunction in cellular models of neurodegenerative diseases. Cell Death Differ 25:542-572
Hou, Yujun; Lautrup, Sofie; Cordonnier, Stephanie et al. (2018) NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency. Proc Natl Acad Sci U S A 115:E1876-E1885
Mattson, Mark P; Arumugam, Thiruma V (2018) Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab 27:1176-1199
Mattson, Mark P; Moehl, Keelin; Ghena, Nathaniel et al. (2018) Intermittent metabolic switching, neuroplasticity and brain health. Nat Rev Neurosci 19:63-80
Raefsky, Sophia M; Furman, Ran; Milne, Ginger et al. (2018) Deuterated polyunsaturated fatty acids reduce brain lipid peroxidation and hippocampal amyloid ?-peptide levels, without discernable behavioral effects in an APP/PS1 mutant transgenic mouse model of Alzheimer's disease. Neurobiol Aging 66:165-176
Nigam, Saket M; Xu, Shaohua; Kritikou, Joanna S et al. (2017) Exercise and BDNF reduce A? production by enhancing ?-secretase processing of APP. J Neurochem 142:286-296
Fang, Evandro F; Lautrup, Sofie; Hou, Yujun et al. (2017) NAD+ in Aging: Molecular Mechanisms and Translational Implications. Trends Mol Med 23:899-916
Raefsky, Sophia M; Mattson, Mark P (2017) Adaptive responses of neuronal mitochondria to bioenergetic challenges: Roles in neuroplasticity and disease resistance. Free Radic Biol Med 102:203-216
Misiak, Magdalena; Vergara Greeno, Rebeca; Baptiste, Beverly A et al. (2017) DNA polymerase ? decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease. Aging Cell 16:162-172

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