title: Synergistic exacerbation of mitochondrial and synaptic dysfunction and resultant learning and memory deficit in a mouse model of diabetic Alzheimer's disease.
abstract: Diabetes is considered to be a risk factor in Alzheimer's disease (AD) pathogenesis. Although recent evidence indicates that diabetes exaggerates pathologic features of AD, the underlying mechanisms are not well understood. To determine whether mitochondrial perturbation is associated with the contribution of diabetes to AD progression, we characterized mouse models of streptozotocin (STZ)-induced type 1 diabetes and transgenic AD mouse models with diabetes. Brains from mice with STZ-induced diabetes revealed a significant increase of cyclophilin D (CypD) expression, reduced respiratory function, and decreased hippocampal long-term potentiation (LTP); these animals had impaired spatial learning and memory. Hyperglycemia exacerbated the upregulation of CypD, mitochondrial defects, synaptic injury, and cognitive dysfunction in the brains of transgenic AD mice overexpressing amyloid-β as shown by decreased mitochondrial respiratory complex I and IV enzyme activity and greatly decreased mitochondrial respiratory rate. Concomitantly, hippocampal LTP reduction and spatial learning and memory decline, two early pathologic indicators of AD, were enhanced in the brains of diabetic AD mice. Our results suggest that the synergistic interaction between effects of diabetes and AD on mitochondria may be responsible for brain dysfunction that is in common in both diabetes and AD.
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Yongfu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Du
authors.initials: D
authors.lastname: Fang
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA College of Life Sciences, Beijing Normal University, Beijing, China.
authors.forename: Changjia
authors.initials: C
authors.lastname: Zhong
authors.affiliation: Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: John Xi
authors.initials: JX
authors.lastname: Chen
authors.affiliation: Department of Pharmacology and Toxicology, and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS, USA.
authors.forename: Shirley ShiDu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications*; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D007859:Learning Disabilities / Q000209:etiology* / Q000473:pathology; D008569:Memory Disorders / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000473:pathology* / Q000502:physiology; D009154:Mutation / Q000235:genetics; D010101:Oxygen Consumption / Q000502:physiology; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology; D013569:Synapses / Q000473:pathology*; D013997:Time Factors
chemical_list: D016564:Amyloid beta-Protein Precursor; D003576:Electron Transport Complex IV
keywords: Alzheimer's disease; cognitive impairment; diabetes; long-term potentiation; mitochondria; synaptic injury
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