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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    • "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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    • "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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    • "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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