Exacerbation of poststroke dementia by type 2 diabetes is associated with synergistic increases of beta-secretase activation and beta-amyloid generation in rat brains.
We examined the effect of type 2 diabetes on stroke-induced Alzheimer's disease-like pathological and behavioral changes in rats. Rats were treated for 2 months with high fat diet (HFD) followed by streptozotocin (STZ) injection to induce type 2 diabetes (HFD-STZ model). Middle cerebral artery occlusion (MCAO) was used to induce cerebral focal ischemia. Animals were divided into four groups: Sham-NPD, Sham-HFD-STZ, MCAO-NPD and MCAO-HFD-STZ. The results showed that HFD-STZ treatment induced obesity, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, hyperglycemia and insulin resistance, characteristics of type 2 diabetes. The performance of rats in the Morris water maze test was impaired in MCAO-NPD and Sham-HFD-STZ rats, indicating cognitive deficits. Hippocampal caspase-3+ and beta amyloid (Abeta+) cell numbers, as well as beta-site amyloid precursor protein-cleaving enzyme (BACE1) levels and activity, increased in both groups. Moreover, HFD-STZ treatment exacerbated stroke-induced cognitive deficits, additively increased MCAO-induced activation of caspase-3, and increased levels of BACE1, C99 and Abeta. However, the level of insulin decreased in MCAO-HFD-STZ rats. These results suggested that type 2 diabetes deteriorated stroke-induced brain damage and cognitive impairment, which might be associated with increased Abeta generation and cytotoxicity. We concluded that type 2 diabetes exacerbated poststroke dementia possibly due to brain injury and synergistic generation of Abeta via activation of BACE1.
Department of Neurobiology, Institute of Biomedical Sciences, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, 138 Yi-Xue-Yuan Road, Shanghai 200032, PR China.
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Zhang
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Pan
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Zhao
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Zhang
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Huang
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Sun
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism; D003704:Dementia / Q000209:etiology* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D006624:Hippocampus / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications*; D007328:Insulin / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D020521:Stroke / Q000150:complications
D016229:Amyloid beta-Peptides; D007328:Insulin; D013311:Streptozocin; D053829:Amyloid Precursor Protein Secretases; C505410:Casp3 protein, rat; D053148:Caspase 3