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Cellular And Molecular Pathogenesis Of Alzheimer
NATIONAL INSTITUTE ON AGING
Total Funding: $ 2,119,076
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. We have also found that redox enzymes in the plasma membrane play important roles in protecting neurons against membrane lipid peroxidation and Abeta toxicity. The latter findings reveal previously unknown molecular targets for the development of novel therapeutic interventions in AD. In other studies we have provided evidence that activation of certain toll-like receptors (TLRs) in neurons and glial cells renders neurons vulnerable to Abeta toxicity and energy deprivation. Moreover,TLRs 2, 3 and 4 have interesting and disparate roles in the regulation of behaviors, including learning and memory and anxiety. 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. In addition, we found that a drug called diazoxide, previously used to treat hypertension,reduces amyloid and tau pathologies and improves cognitive function in our 3xTgAD mouse model of AD. 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. Our recent findings suggest that an excitatory imbalance, resulting from reduced GABAergic inhibition, is an early and pivotal event in AD pathogenesis. We recently demonstrated a therapeutic benefit of drugs used to improve glycemic control in animal models of diabetes and Alzheimer's disease, and we have initiated a clinical trial of one of these drugs, Exenatide, in human subjects with mild cognitive impairment or early stage Alzheimer's disease.
28 Resulting Publications
Marc Gleichmann; Yongqing Zhang; William H Wood; Kevin G Becker; Mohamed R Mughal; Michael J Pazin; Henriette van Praag; Tali Kobilo; Alan B Zonderman; Juan C Troncoso; et al.Neurobiology of aging 2012;33(1):205.e1-18.
Grace E Stutzmann; Mark P MattsonPharmacological reviews 2011;63(3):700-27.
Simonetta Camandola; Mark P MattsonBiochimica et biophysica acta 2011;1813(5):965-73.
Eitan Okun; Kathleen J Griffioen; Mark P MattsonTrends in neurosciences 2011;34(5):269-81.
Carola Romberg; Mark P Mattson; Mohamed R Mughal; Timothy J Bussey; Lisa M SaksidaThe Journal of neuroscience : the official journal of the Society for Neuroscience 2011;31(9):3500-7.
Dimitrios Kapogiannis; Mark P MattsonLancet neurology 2011;10(2):187-98.
Dong-Gyu Jo; Thiruma V Arumugam; Ha-Na Woo; Jong-Sung Park; Sung-Chun Tang; Mohamed Mughal; Dong-Hoon Hyun; Jun-Hyung Park; Yun-Hyung Choi; A-Ryeong Gwon; et al.Neurobiology of aging 2010;31(6):917-25.
Eitan Okun; Mark P Mattson; Thiruma V ArumugamNeuromolecular medicine 2010;12(2):164-78.
K Conant; Y Wang; A Szklarczyk; A Dudak; M P Mattson; S T LimNeuroscience 2010;166(2):508-21.
Marc Gleichmann; Mark P MattsonNeuromolecular medicine 2010;12(1):44-7.
Vivian W Chow; Mark P Mattson; Philip C Wong; Marc GleichmannNeuromolecular medicine 2010;12(1):1-12.
Alexandra Auffret; Vanessa Gautheron; Mark P Mattson; Jean Mariani; Catherine RoviraJournal of Alzheimer's disease : JAD 2010;19(3):1021-33.
Mark P MattsonScience signaling 2010;3(114):pe10.
Dong Liu; Michael Pitta; Jong-Hwan Lee; Balmiki Ray; Debomoy K Lahiri; Katsutoshi Furukawa; Mohamed Mughal; Haiyang Jiang; Julissa Villarreal; Roy G Cutler; et al.Journal of Alzheimer's disease : JAD 2010;22(2):443-57.
Mark P MattsonExperimental gerontology 2009;44(10):625-33.
Vanessa Gautheron; Alexandra Auffret; Mark P Mattson; Jean Mariani; Béatrice Vernet-der GarabedianJournal of neuroscience methods 2009;181(2):235-40.
Eitan Okun; Kathleen J Griffioen; Justin D Lathia; Sung-Chun Tang; Mark P Mattson; Thiruma V ArumugamBrain research reviews 2009;59(2):278-92.
Emmette R Hutchison; Eitan Okun; Mark P MattsonNeuromolecular medicine 2009;11(3):153-61.
Sung-Chun Tang; Justin D Lathia; Pradeep K Selvaraj; Dong-Gyu Jo; Mohamed R Mughal; Aiwu Cheng; Dominic A Siler; William R Markesbery; Thiruma V Arumugam; Mark P MattsonExperimental neurology 2008;213(1):114-21.
Ilya Bezprozvanny; Mark P MattsonTrends in neurosciences 2008;31(9):454-63.
Alexis M Stranahan; Thiruma V Arumugam; Roy G Cutler; Kim Lee; Josephine M Egan; Mark P MattsonNature neuroscience 2008;11(3):309-17.
Rhonda L Nelson; Zhihong Guo; Veerendra Madala Halagappa; Michelle Pearson; Audrey J Gray; Yasuji Matsuoka; Martin Brown; Bronwen Martin; Titilola Iyun; Stuart Maudsley; et al.Experimental neurology 2007;205(1):166-76.
Mark P MattsonNature 2004;430(7000):631-9.
P Chen; M Ganguli; B H Mulsant; S T DeKoskyArchives of general psychiatry 1999;56(3):261-6.
V Chandra; M Ganguli; G Ratcliff; R Pandav; S Sharma; S Belle; C Ryan; C Baker; S DeKosky; L NathAging (Milan, Italy) 1998;10(5):349-57.
M Ganguli; L A Burmeister; E C Seaberg; S Belle; S T DeKoskyBiological psychiatry 1996;40(8):714-25.
M Ganguli; E C Seaberg; G G Ratcliff; S H Belle; S T DeKoskyNeuroepidemiology 1996;15(1):42-50.
S H Belle; E C Seaberg; M Ganguli; G Ratcliff; S DeKosky; L H Kuller
Effect of education and gender adjustment on the sensitivity and specificity of a cognitive screening battery for dementia: results from the MoVIES Project. Monongahela Valley Independent Elders Survey.Neuroepidemiology 1996;15(6):321-9.
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