The quality control of protein homoeostasis deteriorates with aging, causing the accumulation of misfolded proteins and neurodegeneration. Thus, in AD (Alzheimer's disease), soluble oligomers, protofibrils and fibrils of the Aβ (amyloid β-peptide) and tau protein accumulate in specific brain regions. This is associated with the progressive destruction of synaptic circuits controlling memory and higher mental function. The primary signalling mechanisms that (i) become defective in AD to alter the normal proteostasis of Aβ and tau, and (ii) initiate a pathophysiological response to cause cognitive decline, are unclear. The IIS [insulin/IGF-1 (insulin-like growth factor 1)-like signalling] pathway is mechanistically linked to longevity, protein homoeostasis, learning and memory, and is emerging to be central to both (i) and (ii). This pathway is aberrantly overactivated in AD brain at the level of increased activation of the serine/threonine kinase Akt and the phosphorylation of its downstream targets, including mTOR (mammalian target of rapamycin). Feedback inhibition of normal insulin/IGF activation of the pathway also occurs in AD due to inactivation of IRS-1 (insulin receptor substrate 1) and decreased IRS-1/2 levels. Pathogenic forms of Aβ may induce aberrant sustained activation of the PI3K (phosphoinositide 3-kinase)/Akt signal in AD, also causing non-responsive insulin and IGF-1 receptor, and altered tau phosphorylation, conformation and function. Reducing IIS activity in animal models by decreasing IGF-1R levels or inhibiting mTOR activity alters Aβ and tau protein homoeostasis towards less toxic protein conformations, improves cognitive function and extends healthy lifespan. Thus normalizing IIS dysfunction may be therapeutically relevant in abrogating Aβ and tau proteotoxicity, synaptic dysfunction and cognitive decline in AD.
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August 2012
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Conference Article|
July 20 2012
Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease
Cora O'Neill;
Cora O'Neill
1
1Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland
1To whom correspondence should be addressed (email[email protected]).
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Aoife P. Kiely;
Aoife P. Kiely
1Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland
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Meghan F. Coakley;
Meghan F. Coakley
1Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland
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Sean Manning;
Sean Manning
1Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland
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Caitriona M. Long-Smith
Caitriona M. Long-Smith
1Department of Biochemistry, BioSciences Institute, University College Cork, Cork, Ireland
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Publisher: Portland Press Ltd
Received:
March 14 2012
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem Soc Trans (2012) 40 (4): 721–727.
Article history
Received:
March 14 2012
Citation
Cora O'Neill, Aoife P. Kiely, Meghan F. Coakley, Sean Manning, Caitriona M. Long-Smith; Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease. Biochem Soc Trans 1 August 2012; 40 (4): 721–727. doi: https://doi.org/10.1042/BST20120080
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