Journal
NEUROBIOLOGY OF DISEASE
Volume 132, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2019.104541
Keywords
Alzheimer's disease; IGF-I; Insulin; Amyloid precursor protein; Insulin resistance
Categories
Funding
- Program for Neurology Research Discovery
- A. Alfred Taubman Medical Research Institute
- Handelman Emerging Scholar Fund
- Robert E. Nederlander Sr. Program for Alzheimer's Research
- National Institutes of Health [T32 DK101357]
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Alzheimer's disease (AD) is a growing problem worldwide, and there are currently no effective treatments for this devastating disease. The neurotrophic growth factors insulin and insulin-like growth factor-I (IGF-I) are currently being investigated as potential therapeutic approaches for AD in preclinical and clinical studies. However, given that the metabolic syndrome (MetS) and diabetes are risk factors for AD, it is unknown how associated insulin resistance (IR) in the brain may impact the effectiveness of these therapies for AD. In this report, we therefore investigated the mechanisms underlying the effects of insulin and IGF-I on AD-associated pathology in the context of IR, with particular emphasis on phosphorylation of amyloid precursor protein (APP), a key step in promoting amyloid plaque formation in AD. Both insulin and IGF-I decreased APP phosphorylation in cultured primary cortical neurons, supporting their therapeutic use in AD. Induction of IR blocked the beneficial effect of insulin and reduced the effect of IGF-I on APP dephosphorylation. These effects were mediated by the phosphatidylinositol 3-kinase (PI3-K)/protein kinase B (Akt) pathway, as inhibition of this pathway during IR restored the effect of IGF-I on APP dephosphorylation. Finally, we explored the translational relevance of these results in vivo by demonstrating that high fat diet fed mice, a robust model of IR and MetS, exhibited the expected increased brain APP phosphorylation. Overall, these data suggest that the beneficial therapeutic effect of insulin and IGF-I on APP phosphorylation is negatively impacted by IR, and suggest that insulin and IGF-I alone may not be appropriate therapies for AD patients with IR, MetS, or diabetes.
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