Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity

Abstract

ObjectivesDiabetes leads to cognitive impairment and is associated with age-related neurodegenerative diseases including Alzheimer's disease (AD). Thus, understanding diabetes-induced alterations in brain function is important for developing early interventions for neurodegeneration. Low-capacity runner (LCR) rats are obese and manifest metabolic risk factors resembling human “impaired glucose tolerance” or metabolic syndrome. We examined hippocampal function in aged LCR rats compared to their high-capacity runner (HCR) rat counterparts.MethodsHippocampal function was examined using proton magnetic resonance spectroscopy and imaging, unbiased stereology analysis, and a Y maze. Changes in the mitochondrial respiratory chain function and levels of hyperphosphorylated tau and mitochondrial transcriptional regulators were examined.ResultsThe levels of glutamate, myo-inositol, taurine, and choline-containing compounds were significantly increased in the aged LCR rats. We observed a significant loss of hippocampal neurons and impaired cognitive function in aged LCR rats. Respiratory chain function and activity were significantly decreased in the aged LCR rats. Hyperphosphorylated tau was accumulated within mitochondria and peroxisome proliferator-activated receptor-gamma coactivator 1α, the NAD+-dependent protein deacetylase sirtuin 1, and mitochondrial transcription factor A were downregulated in the aged LCR rat hippocampus.InterpretationThese data provide evidence of a neurodegenerative process in the hippocampus of aged LCR rats, consistent with those seen in aged-related dementing illnesses such as AD in humans. The metabolic and mitochondrial abnormalities observed in LCR rat hippocampus are similar to well-described mechanisms that lead to diabetic neuropathy and may provide an important link between cognitive and metabolic dysfunction.

Metabolic syndrome and adverse clinical outcomes in patients with bipolar disorder

“…The current results supported our hypothesis that patients with comorbid bipolar disorder and MetS associate with the severity of neurodegenerative processes and cognitive impairment than those without [23, 50]. MetS can elicit inflammatory response (increase in the number of reactive astrocytes as well as the levels of interleukin-1-beta and tumor necrosis factor-alpha) and oxidative stress (reactive oxygen species and lipid peroxidation), causing a reduction in the number of neurons in the temporal cortex and hippocampus [23, 51]. Hyperglycemia can directly affect neuron myelin or axons and the structure and function of endoneurial microvessels, which can then induce fiber changes by altering the blood–nerve barrier and inducing hypoxia or ischemia or through unknown mechanisms [52].…”

“…In addition to the leading hypothesis of dopamine receptor hypersensitivity with antipsychotic treatment, a crucial pathophysiological theory of tardive dyskinesia involves neurotoxicity [59]. MetS can elicit inflammatory response and oxidative stress, reducing the number of neurons [23, 51]; animal studies have shown that tardive dyskinesia is associated with inflammation and apoptosis [60, 61]. Furthermore, the potent antioxidants vitamins E and B6 as well as piracetam have been shown to alleviate the severity of tardive dyskinesia in randomized, double-blind, placebo-controlled studies [62, 63].…”

Diabetes and Cognitive Impairment

“…2). Interestingly, inhibitors of Mt bioenergetics produce a pattern of metabolic changes that mimics that observed in brains of AD patients [37•, 61], supporting the critical role of Mt in normal cognitive function. This decline in Mt function is associated with epigenetic silencing of nuclear or Mt DNA and failure of DNA repair that can result in neuronal failure [62].…”

“…There is evidence of MRI abnormalities including a reduction in hippocampal volumes in both animal models [37•] and human subjects [33, 34, 38–40] with IGR. With improvement in glycemic control, there is stabilization of the rate of brain atrophy [33, 34].…”

“…In LCR compared to HCR rats, using a creatine and phosphocreatine (Cr) internal standard, glutamate/tCr, myo -inositol/tCr, taurine/tCr, glycerophosphocholine, and phosphocholine/tCr ratios were significantly higher, whereas glutamine/tCr was reduced. There was no difference in the glucose/tCr and N-acetylaspartate (NAA)/tCr ratios [37•]. In human studies, the following general conclusions about impaired cognition in T2DM can be reached: NAA levels are mostly decreased, indicating loss of neuronal integrity; myoinositol levels are increased; excitatory neurotransmitters (glutamate and glycine) are increased; and inhibitory neurotransmitters (GABA) are decreased, consistent with abnormal pain regulation [43].…”