Intrahippocampal administration of A beta(1-40) impairs spatial learning and memory in hyperglycemic mice.
Age-related neurodegenerative dementia, particularly Alzheimer's disease (AD), may be exacerbated by several interacting risk factors including genetic predisposition, beta amyloid (A beta) protein accumulation, environmental toxins, head trauma, and abnormal glycolytic metabolism. We examined the spatial learning and memory effects of A beta(1-40) administration on hyperglycemic mice by their performance in the Morris water maze. Chronic hyperglycemia was induced in male C57BL/6J mice to mimic diabetes mellitus by intraperitoneal injection of streptozotocin (STZ), which specifically destroys pancreatic beta-islet cells. Ten days after STZ treatment, intrahippocampal infusion of vehicle, monomer, or oligomer A beta(1-40) was given to these hyperglycemic mice. Our results demonstrate that in comparison with vehicle or monomer A beta(1-40), oligomer A beta(1-40) induced significant deficits of spatial learning and memory in hyperglycemic mice. Apoptotic signals were identified in the CA1 and dentate gyrus of hippocampus in hyperglycemic mice. A beta accumulation, oxidative stress, and apoptosis in the CA1 region were more intensive in hyperglycemic mice than that in normoglycemic mice after acute treatment with oligomer A beta(1-40) peptide treatment. These results indicate that CA1 apoptosis was enhanced by oxidative stress resulting from accumulation of A beta. Considered together, these findings suggest that hyperglycemic mice are more vulnerable to the A beta-induced-oxidative stress than normal subjects. We therefore propose that A beta accumulation would be enhanced by hyperglycemia, and the oxidative stress caused by A beta accumulation would in turn enhance the AD symptoms.
Huang
Hei-Jen
HJ
Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
Liang
Ken-Chen
KC
Chen
Chie-Pein
CP
Chen
Chiung-Mei
CM
Hsieh-Li
Hsiu Mei
HM
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D004193:Discrimination Learning / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006943:Hyperglycemia / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology*
D016229:Amyloid beta-Peptides; D001786:Blood Glucose; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)