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

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Phosphorylation
Amyloid beta-Protein Precursor
Amyloid
Transgenic Mice
Insulin Receptor Substrate Proteins
Insulin
Glycogen Synthase Kinase 3
Prealbumin
Pathology
Phosphoric Monoester Hydrolases
Insulin Resistance
Carrier Proteins
Alzheimer Disease
Animals
Phosphotransferases
Therapeutics

Keywords

  • Alzheimer’s disease
  • diabetes
  • insulin signalling

Cite this

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. / Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice. In: Biochemical and Biophysical Research Communications. 2009 ; Vol. 386, No. 1. pp. 257–262.
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Killick, R, Scales, G, Leroy, K, Causevic, M, Hooper, C, Irvine, EE, Choudhury, AI, Drinkwater, L, Kerr, F, Al-Qassab, H, Stephenson, J, Yilmaz, Z, Giese, KP, Brion, J-P, Withers, DJ & Lovestone, S 2009, 'Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice', Biochemical and Biophysical Research Communications, vol. 386, no. 1, pp. 257–262. https://doi.org/10.1016/j.bbrc.2009.06.032

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.

In: Biochemical and Biophysical Research Communications, Vol. 386, No. 1, 14.08.2009, p. 257–262.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice

AU - Killick, Richard

AU - Scales, Georgie

AU - Leroy, Karelle

AU - Causevic, Mirsada

AU - Hooper, Claudie

AU - Irvine, Elaine E.

AU - Choudhury, Agharul I.

AU - Drinkwater, Laura

AU - Kerr, Fiona

AU - Al-Qassab, Hind

AU - Stephenson, John

AU - Yilmaz, Zehra

AU - Giese, K. Peter

AU - Brion, Jean-Pierre

AU - Withers, Dominic J.

AU - Lovestone, Simon

PY - 2009/8/14

Y1 - 2009/8/14

N2 - 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.

AB - 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.

KW - Alzheimer’s disease

KW - diabetes

KW - insulin signalling

U2 - 10.1016/j.bbrc.2009.06.032

DO - 10.1016/j.bbrc.2009.06.032

M3 - Article

VL - 386

SP - 257

EP - 262

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 1

ER -