Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice

King's College London, MRC Centre for Neurodegenerative Research, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 07/2009; 386(1):257-62. DOI: 10.1016/j.bbrc.2009.06.032
Source: PubMed


As impaired insulin signalling (IIS) is a risk factor for Alzheimer's disease we crossed mice (Tg2576) over-expressing human amyloid precursor protein (APP), with insulin receptor substrate 2 null (Irs2(-/-)) mice which develop insulin resistance. The resulting Tg2576/Irs2(-/-) animals had increased tau phosphorylation but a paradoxical amelioration of Abeta pathology. An increase of the Abeta binding protein transthyretin suggests that increased clearance of Abeta underlies the reduction in plaques. Increased tau phosphorylation correlated with reduced tau-phosphatase PP2A, despite an inhibition of the tau-kinase glycogen synthase kinase-3. Our findings demonstrate that disruption of IIS in Tg2576 mice has divergent effects on pathological processes-a reduction in aggregated Abeta but an increase in tau phosphorylation. However, as these effects are accompanied by improvement in behavioural deficits, our findings suggest a novel protective effect of disrupting IRS2 signalling in AD which may be a useful therapeutic strategy for this condition.

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Available from: Jean-Pierre Brion
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    • "This suggests that tau pathology may be directly influenced by dietary factors, rather than by diabetesrelated metabolic changes. It has been shown that impaired neuronal insulin signaling reduces the accumulation of Aβ and protects AD mice from premature death [16] [20]. However, the role of insulin in the brain differs from that in periphery, suggesting that the link between peripheral and central insulin resistance is complex. "
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    ABSTRACT: Alzheimer’s disease and type 2 diabetes mellitus are risk factors for each other. To investigate the effects of both genetic and high-fat-induced diabetic phenotype on the expression and exon 10 splicing of tau, we used the Alzheimer’s disease mouse model (APdE9) cross-bred with the type 2 diabetes mouse model over-expressing insulin-like growth factor 2 in the pancreas. High-fat diet, regardless of the genotype, significantly induced the expression of four repeat tau mRNA and protein in the temporal cortex of female mice. The mRNA levels of three repeat tau were also significantly increased by high-fat diet in the temporal cortex, although three repeat tau expression was considerably lower as compared to four repeat tau. Moreover, high-fat diet significantly increased the mRNA ratio of four repeat tau vs. three repeat tau in the temporal cortex of these mice. All of these effects were independent of the peripheral hyperglycemia, hyperinsulinemia, and insulin resistance. Increased four repeat tau and three repeat tau levels significantly associated with impaired memory and reduced rearing in the female mice. High-fat diet did not affect neuroinflammation, Akt/GSK3β signaling pathway or the expression of tau exon 10 splicing enhancers in the temporal cortex. Our study suggests that the high-fat diet independently of type 2 diabetes or Alzheimer’s disease background induces the expression and exon 10 inclusion of tau in the brain of female mice.
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    • "This apparent anomaly is consistent with the study demonstrating that IRS 2 is a negative regulator of memory function and restricts dendritic spine generation [61]. Deletion of Irs2 reduces amyloid deposition and rescues behavioral deficits in APP transgenic mice [62] and increases in Irs2 in this study are consistent with negative effects on learning and memory. Although in a nonsignificative manner, cinnamon blunted the HF/HFr diet effects on anxiety in EPM. "
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    ABSTRACT: Insulin resistance leads to memory impairment. Cinnamon (CN) improves peripheral insulin resistance but its effects in the brain are not known. Changes in behavior, insulin signaling and Alzheimer-associated mRNA expression in the brain were measured in male Wistar rats fed a high fat/high fructose (HF/HFr) diet to induce insulin resistance, with or without CN, for 12 weeks. There was a decrease in insulin sensitivity associated with the HF/HFr diet that was reversed by CN. The CN fed rats were more active in a Y maze test than rats fed the control and HF/HFr diets. The HF/HFr diet fed rats showed greater anxiety in an elevated plus maze test that was lessened by feeding CN. The HF/HFr diet also led to a down regulation of the mRNA coding for GLUT1 and GLUT3 that was reversed by CN in the hippocampus and cortex. There were increases in Insr, Irs1 and Irs2 mRNA in the hippocampus and cortex due to the HF/HFr diet that were not reversed by CN. Increased peripheral insulin sensitivity was also associated with increased glycogen synthase in both hippocampus and cortex in the control and HF/HFr diet animals fed CN. The HF/HFr diet induced increases in mRNA associated with Alzheimers including PTEN, Tau and amyloid precursor protein (App) were also alleviated by CN. In conclusion, these data suggest that the negative effects of a HF/HFr diet on behavior, brain insulin signaling and Alzheimer-associated changes were alleviated by CN suggesting that neuroprotective effects of CN are associated with improved whole body insulin sensitivity and related changes in the brain.
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    • "These include three upregulated genes (Prkab2 1.2×, Rheb, 1.3× and Mapk10, 1.3×) and three downregulated genes (Fasn -1.32×, Pygm -1.5× and Irs4 -2.0). Insulin receptor substrate 4 (Irs4) is the most downregulated gene in the insulin signaling pathway and is of particular interest as Irs genes have been shown to impact phosphorylation of tau, a crucial step in the generation of neurofibrillary tangles [58,59]. Previous studies have localized Irs4 to specific sets of neurons in the hypothalamus [60,61] and Allen Brain Atlas for mouse shows expression of Irs4 mainly in the hypothalamus and at lower levels in pallidum. "
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