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

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

Authors

Richard Killick

Georgie Scales

Karelle Leroy

Mirsada Causevic

Claudie Hooper

Elaine E Irvine

Agharul I Choudhury

Laura Drinkwater

Hind Al-Qassab

John Stephenson

Zehra Yilmaz

K Peter Giese

Jean-Pierre Brion

Dominic J Withers

Simon Lovestone



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 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.

Citation

Killick, R., Scales, G., Leroy, K., Causevic, M., Hooper, C., Irvine, E. E., …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

Journal Article Type Article
Online Publication Date Jun 10, 2009
Publication Date 2009-08
Deposit Date Aug 19, 2016
Publicly Available Date Mar 16, 2020
Journal Biochemical and Biophysical Research Communications
Print ISSN 0006-291X
Electronic ISSN 1090-2104
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 386
Issue 1
Pages 257-262
DOI https://doi.org/10.1016/j.bbrc.2009.06.032
Keywords Alzheimer’s disease; Diabetes; Insulin signalling; Tau; APP; Abeta; GSK-3; PP2a; Transthyretin; Irs2
Public URL http://researchrepository.napier.ac.uk/Output/355818

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