Alzheimer's disease (AD) is associated with brain insulin resistance and insulin deficiency, whereas Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance. This study assesses the degree to which T2DM causes AD-type neurodegeneration. In a C57BL/6 mouse model of obesity and T2DM, we characterized the histopathology, gene expression, and insulin and insulin-like growth factor (IGF)-receptor binding in temporal lobe. High fat diet (HFD) feeding for 16 weeks doubled mean body weight, caused T2DM, and marginally reduced mean brain weight. These effects were associated with significantly increased levels of tau, IGF-I receptor, insulin receptor substrate-1 (IRS-1), IRS-4, ubiquitin, glial fibrillary acidic protein, and 4-hydroxynonenol, and decreased expression of beta-actin. HFD feeding also caused brain insulin resistance manifested by reduced BMAX for insulin receptor binding, and modestly increased brain insulin gene expression. However, HFD-fed mouse brains did not exhibit AD histopathology, increases in amyloid-beta or phospho-tau, or impairments in IGF signaling or acetylcholine homeostasis. Obesity and T2DM cause brain atrophy with insulin resistance, oxidative stress, and cytoskeleton degradation, but the absence of many features that typify AD suggests that obesity and T2DM may contribute to, but are not sufficient to cause AD.
"As one approach leading to weight gain, an extremely high-fat diet (HFD, 60% calorie from fat) was previously shown to induce a remarkable brain insulin resistance as well as spatial memory impairment in a normal mouse or a transgenic mouse model of AD (Ho et al., 2004; Moroz et al., 2008; Leboucher et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Osteoporosis is negatively correlated with body mass, whereas both osteoporosis and weight loss occur at higher incidence during the progression of Alzheimer's disease (AD) than the age-matched non-dementia individuals. Given that there is no evidence that being overweight is associated with AD-type cognitive dysfunction, we hypothesized that moder-ate weight gain might have a protective effect on the bone loss in AD without exacerbating cognitive dysfunction. In this study, feeding a high-fat diet (HFD, 45% calorie from fat) to female APP/PS1 transgenic mice, an AD animal model, induced weight gain. The bone mineral density, microarchitecture, and biomechanical properties of the femurs were then evaluated. The results showed that the middle-aged female APP/PS1 transgenic mice were susceptible to osteoporosis of the femoral bones and that weight gain significantly enhanced bone mass and mechanical properties. Notably, HFD was not detrimental to brain insulin signaling and AβPP processing, as well as to exploration ability and working, learning, and memory performance of the transgenic mice measured by T maze and Mor-ris water maze, compared with the mice fed a normal-fat diet (10% calorie from fat). In addition, the circulating levels of leptin but not estradiol were remarkably elevated in HFD-treated mice. These results suggest that a body weight gain induced by the HFD feeding regimen significantly improved bone mass in female APP/PS1 mice with no detriments to exploration ability and spatial memory, most likely via the action of elevated circulating leptin.
"Recent studies have shown differing results on whether DIO enhances tau phosphorylation in WT mice   . Both Moroz's study (60%-fat chow, fed for 4 months from 1 month of age) and Leboucher's study (59%-fat chow, fed for 5 months from 2 months of age) reported that DIO increased the level of tau but did not induce tau phosphorylation  . On the other hand, Bhat's study (21%- fat chow, fed for 2 months from 4 months of age) and our present study (15.3%-fat chow, fed for 7 months from 3 months of age) showed that DIO increased tau phosphorylation in WT mice . "
[Show abstract][Hide abstract] ABSTRACT: Accumulating evidence indicates that obesity is an independent risk factor for developing Alzheimer disease (AD). Recent studies have shown that diet-induced obesity (DIO) enhances AD-related pathologies in transgenic mouse models of the disease. DIO increases amyloid β (Aβ) deposition in amyloidogenic transgenic mice and enhances tau phosphorylation in tau transgenic mice. However, it remains unclear whether DIO also enhances AD-related pathological processes in wild-type (WT) mice. In this study, we examined the effects of DIO on Aβ and tau pathology in WT mice using immunohistochemistry. In addition, we evaluated the protective effect of voluntary exercise on the DIO-induced pathological changes. DIO caused tau phosphorylation and astroglial activation in the hippocampus in WT mice. Interestingly, these changes were associated with enhanced astrocytic leptin receptor (LepR) expression and mild microgliosis, but not Aβ accumulation. Although phosphorylated tau staining was only observed in the hippocampus, astrogliosis and microgliosis were present in both the amygdala and hippocampus. However, no apparent neuronal loss was observed. Voluntary exercise prevented these DIO-induced pathological changes. Our results demonstrate for the first time that DIO causes tau phosphorylation and that astrocytic LepR might be involved in the pathological process in WT mouse hippocampus. Our findings also suggest that physical exercise is a promising strategy for the prevention of AD in patients with obesity.
"However, how peripheral insulin dysfunction results in central PP2A inhibition remains to be elucidated. Moreover, Moroz et al. have demonstrated that HFD-induced T2DM leads to an increase in mRNA levels of IRS-1 and IRS- 4 in the brain of non-transgenic mice (Moroz et al., 2008). By contrast, Bhat and Thirumangalakudi have reported a decrease in IRS-1 levels in the brain of HFC-treated mice (Bhat and Thirumangalakudi, 2013). "
[Show abstract][Hide abstract] ABSTRACT: The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.
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