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A potential therapeutic role for insulin-like growth factor-I (IGF-I) in Alzheimer’s Disease


Bristol Medical School

About the Project

Rationale
Early loss of short-term memory and later, cognitive failure and confusion, and loss of independence are clinical hallmarks of Alzheimer’s disease (AD), a disease mainly of later life, which is characterised by distinct neuropathology involving amyloid β (Aβ) peptide and the hyper-phosphorylation of tau protein neurofibrillary tangles [1]. The activity of insulin-like growth factor I (IGF-I), which modulates many cellular processes including, proliferation, differentiation, energy metabolism, and apoptosis, is lost in later life and may play an important role in the development of AD: reduced IGF-I signalling increased Aβ deposition [2, 3] and was associated with phosphorylated tau [4] increased oxidative stress, neuro-inflammation and apoptosis [5]. IGF-I may also have a role in the clearance of Aβ through interaction with several Aβ degrading enzymes, whilst IGF-I concentration is associated with cognitive decline[6,7].

Aims & Objectives
This study will explore the possible associations between IGF-1 signalling and the neuropathology of AD to inform the potential therapeutic potential of IGF-I as a novel strategy to promoting the clearance of Aβ from the brain, as well as alleviate other pathogenic mechanisms that may protect against AD.

Methods
The project will take three different approaches, in vitro, in vivo and in silico studies, initially involving some examination of ex vivo post-mortem brain tissue homogenates to characterise the relationship between IGF-I activity and IGF-IR signalling mediators and neuropathological hallmarks of AD. Findings would be explored further and validated using cultured nerve cells in vitro to assess the effects of IGF-I on the level and activity of Aβ-degrading enzymes.

References

1. DeTure, M.A. and D.W. Dickson, The neuropathological diagnosis of Alzheimer's disease. Mol Neurodegener, 2019. 14(1): p. 32.

2. Carro, E., et al., Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med, 2002. 8(12): p. 1390-7.

3. Ashpole, N.M., et al., Growth hormone, insulin-like growth factor-1 and the aging brain. Exp Gerontol, 2015. 68: p. 76-81.

4. Gasparini, L., et al., Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci, 2001. 21(8): p. 2561-70.

5. Bedse, G., et al., Aberrant insulin signaling in Alzheimer's disease: current knowledge. Front Neurosci, 2015. 9: p. 204.

6. Kalmijn, S., et al., A prospective study on circulating insulin-like growth factor I (IGF-I), IGF-binding proteins, and cognitive function in the elderly. J Clin Endocrinol Metab, 2000. 85(12): p. 4551-5.

7. Okereke, O., et al., Plasma IGF-I levels and cognitive performance in older women. Neurobiol Aging, 2007. 28(1): p. 135-42.

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