| dc.description.abstract | The brain has high energy demands, which are met by the complete oxidation of glucose, the obligatory energy substrate for the brain under physiological conditions. Glucose oxidative metabolism consists of cytosolic processes that generate pyruvate, TCA cycle that provides reducing equivalents, and mitochondrial oxidative phosphorylation that converts energy to ATP. Consistent with the crucial role of energy metabolism in the maintenance of brain function, impaired glucose metabolism, and mitochondrial dysfunction have been implicated in the pathobiology of many brain disorders, including Alzheimer’s disease (AD) and diabetes. In this dissertation, the molecular mechanisms underlying altered glucose metabolism in the brains at genetic risk for AD and perturbed mitochondrial function in diabetes-associated brain dysfunction are studied. In the first study, the impact of human ApoE isoforms, which confer differential risk for AD, on brain glucose metabolism were investigated in human ApoE gene-targeted replacement mice (hApoE-TR). Gene expression profiling of the cortical RNA extracted from hApoE-TR mice revealed that ApoE2-bearing brains exhibited the most robust, while ApoE4 brains were associated with the most, deficient profile on both the uptake and metabolism of glucose. In particular, the three ApoE brains differed in the expression of hexokinase, which acts as the “gateway” enzyme by catalyzing the conversion of glucose to glucose-6-phosphate, a branch point metabolite that can be directed to glycolysis, glycogen synthesis, and the pentose phosphate pathway. Ingenuity pathway analysis (IPA) predicted that PPAR-γ/PGC-1α signaling pathway could be enhanced in the ApoE2 brain and attenuated in the ApoE4 brain. In line with the prediction, PGC-1α overexpression ameliorated ApoE4-associated bioenergetic deficits. Furthermore, forced expression of ApoE2 counteracted the detrimental effects induced by ApoE4 as demonstrated by the marked improvement in glycolytic function, mitochondrial respiration, and the concurrent increase in ATP levels in ApoE4-expressing cells transfected with ApoE2 as compared to those transfected with mock control. Taken together, in the first study, we discovered a key cytosolic point in glucose metabolism that is differentially modulated by human ApoE isoforms, which could serve as a potential mechanism underlying their discrete risk impact in AD. In the second study, the potential roles of cyclophilin D (CypD), a critical regulator of mitochondrial permeability transition (mPT), in diabetes-related mitochondrial abnormalities and cognitive dysfunction were investigated using mice injected with streptozotocin (STZ), a mouse model of type 1 diabetes. Brain mitochondria from STZ-treated mice exhibited a significant increase in CypD expression, a marked decrease in mitochondrial respiratory function, as well as deficits in spatial learning and memory. Notably, genetic deletion of CypD significantly attenuated diabetes-associated defects in mitochondrial function and cognitive deficits. By contrast, upregulation of CypD and defects in mitochondrial respiration were greatly exacerbated in the brains of AD transgenic mice, suggesting AD and diabetes may have synergistic effects on CypD expression and mitochondrial dysfunction. As a result of an exacerbation of mitochondrial dysfunction, cognitive decline was greatly accelerated in AD transgenic mice injected with STZ. Collectively, results obtained from the second study provide new insights into the mechanisms underlying brain mitochondrial malfunction and cognitive impairment, both of which are common pathological features in AD and diabetes. | |
