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

Richard Killick, Georgie Scales, Karelle Leroy, Mirsada Causevic, Claudie Hooper, Elaine E. Irvine, Agharul I. Choudhury, Laura Drinkwater, Fiona Kerr, Hind Al-Qassab, John Stephenson, Zehra Yilmaz, K. Peter Giese, Jean-Pierre Brion, Dominic J. Withers, Simon Lovestone

Research output: Contribution to journalArticle

Abstract

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 Aß pathology. An increase of the Aß binding protein transthyretin suggests that increased clearance of Aß 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 Aß 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.
Original languageEnglish
Pages (from-to)257–262
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume386
Issue number1
DOIs
Publication statusPublished - 14 Aug 2009

Keywords

  • Alzheimer’s disease
  • diabetes
  • insulin signalling

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    Killick, R., Scales, G., Leroy, K., Causevic, M., Hooper, C., Irvine, E. E., Choudhury, A. I., Drinkwater, L., Kerr, F., Al-Qassab, H., Stephenson, J., Yilmaz, Z., Giese, K. P., Brion, J-P., Withers, D. J., & Lovestone, S. (2009). Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. Biochemical and Biophysical Research Communications, 386(1), 257–262. https://doi.org/10.1016/j.bbrc.2009.06.032