Amyloid, C1q, Alzheimer's disease, apoptosis, successful aging, dementia
The research of the Cotman laboratory is aimed toward understanding the mechanisms causing neuronal degeneration in Alzheimer’s disease (AD) and the development of interventions to promote successful aging. We have been investigating the possibility that the accumulation of risk factors in the aged brain such as beta-amyloid and oxidative damage activate pathways associated with apoptosis. As predicted from cell culture models, caspases and related pathways are up regulated and caspase cleavage products of proteins such fodrin; APP and tau accumulate in the AD brain. In the case of fodrin the accumulation parallels that of tangle formation, suggesting that like tangles this mechanism correlates with cognitive decline (Rohn, 2000).
In parallel, we have been investigating possible behavioral interventions that may aid the brain in aging successfully. We suggest that exercise and environmental enrichment can have beneficial effects on brain function and heath. Our findings show that Brain Derived Neurotrophic Factor (BDNF), a trophic factor known to support neuronal survival and plasticity, is induced with a few days of voluntary running in animal studies. In rodents and aged canines (dogs), current studies are investigating the mechanisms and functional consequences of this simple and widely practiced behavior (Cotman and Berchtold, 2002). We are finding that environmental enrichment particularly if combined with antioxidants can result in a slowing of rate of decline in learning and memory in the aged canine (Milgram, et al. in press). One of the current goals of our research is to evaluate such intervention strategies in elderly humans in collaboration with other investigators in the field. Specific training. Training is provided in basic cell culture biochemical methods as well as neuroanatomical methods applied to the study of the aging and AD brain. We also participate in the design and performance of clinical trials in collaboration with others. Collaborators include Kawas, Tenner, Glabe, and Sheu.
G. Aleph Prieto, Brian H. Trieu, Cindy T. Dang, Tina Bilousova, Karen H. Gylys, Nicole C. Berchtold, Gary Lynch, Carl W. Cotman; Pharmacological Rescue of Long-Term Potentiation in Alzheimer Diseased Synapses; J Neurosci. 2017 Feb 1; 37(5): 1197–1212. doi: 10.1523/JNEUROSCI.2774-16.2016 PMCID: PMC5296796
Christopher W. Butler, Ashley A. Keiser, Janine L. Kwapis, Nicole C. Berchtold, Vanessa L. Wall, Marcelo A. Wood, Carl W. Cotman; Exercise opens a temporal window for enhanced cognitive improvement from subsequent physical activity; Learn Mem. 2019 Dec; 26(12): 485–492. Published online 2019 Dec. doi: 10.1101/lm.050278.119 PMCID: PMC6859826
Nicole C. Berchtold, G. Aleph Prieto, Michael Phelan, Daniel L. Gillen, Pierre Baldi, David A. Bennett, Aron S. Buchman, Carl W. Cotman; Hippocampal gene expression patterns linked to late-life physical activity oppose age and AD-related transcriptional decline. Neurobiol Aging. Author manuscript; available in PMC 2020 Jun 1. Published in final edited form as: Neurobiol Aging. 2019 Jun; 78: 142–154. Published online 2019 Feb 20. doi: 10.1016/j.neurobiolaging.2019.02.012; PMCID: PMC6901108
Shikha Snigdha, G. Aleph Prieto, Arpine Petrosyan, Brad M. Loertscher, André P. Dieskau, Larry E. Overman, Carl W. Cotman; H3K9me3 Inhibition Improves Memory, Promotes Spine Formation, and Increases BDNF Levels in the Aged Hippocampus; J Neurosci. 2016 Mar 23; 36(12): 3611–3622. doi: 10.1523/JNEUROSCI.2693-15.2016 PMCID: PMC4804016
Shikha Snigdha, Michael A. Yassa, Christina deRivera, Norton W. Milgram, Carl W. Cotman; Pattern separation and goal-directed behavior in the aged canine; Learn Mem. 2017 Mar; 24(3): 123–131. Published online 2017 Mar. doi: 10.1101/lm.043422.116 PMCID: PMC5311386
Diane M. Jacobs, Ronald G. Thomas, David P. Salmon, Shelia Jin, Howard H. Feldman, Carl W. Cotman, Laura D. Baker, for the Alzheimer's Disease Cooperative Study EXERT Study Group, for the Alzheimer's Disease Neuroimaging Initiative; Development of a novel cognitive composite outcome to assess therapeutic effects of exercise in the EXERT trial for adults with MCI: The ADAS-Cog-Exec; Alzheimers Dement (N Y) 2020; 6(1): e12059. Published online 2020 Sep 9. doi: 10.1002/trc2.12059 PMCID: PMC7507362
R01 AG051807 (Cotman/Wood)
Exercise-induced epigenetic mechanisms underlying neuronal plasticity and cognition
Examine epigenetic mechanisms controlling a molecular memory for exercise.
2 T32 AG00096 (Cotman)
Training in the Neurobiology of Aging
This training program in the Neurobiology of Aging is designed to provide high quality research training for select pre and postdoctoral students to prepare them for successful independent careers on the basic mechanisms in the neurobiology of aging.
Epigenetic suppression of histone Methylation reverses age and AD-related cognitive decline.
We will test the possibility that H3K9me3 is a key nodal repression point for cognitive decline associated with aging and AD, and that reducing H3K9me3 restores lost cognition in wild type and AD transgenic mouse models.
Single Cell Analysis of Aging-Associated 4D Nucleome in the Human Hippocampus
The proposed research examines the molecular 4D nucleome changes that occur in human hippocampus during the course of aging, and the positive effects of physical activity. This project will produce multi-omics cell atlases of the human hippocampus to delineate molecular profiles of normal aging, and uncover potential transcriptional regulatory programs that are impacted by aging.
Epigenomic Analysis of Neural Circuits in Alzheimer’s Disease Mouse Models
This project examines the molecular changes that occur in the course of AD using mouse models that mimic this neurodegenerative condition. The results could lead to new biomarkers for early detection of AD and candidate drug targets for development of effective treatments.