Journal
FRONTIERS IN NEUROSCIENCE
Volume 13, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fnins.2019.00629
Keywords
Alzheimer's disease; type 2 diabetes; insulin; phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K); Akt (Protein kinase B, PKB); glucose metabolism; neuroinflammation; autophagy
Categories
Funding
- Academy of Finland [288659, 307866, 315459]
- Sigrid Juselius Foundation
- Yrjo Jahnsson Foundation [20187070]
- Strategic Neuroscience Funding of the University of Eastern Finland
- Neurocenter Finland - AlzTrans pilot project
- Academy of Finland (AKA) [288659, 288659] Funding Source: Academy of Finland (AKA)
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Alzheimer's disease (AD) and type 2 diabetes (T2D) are both diseases with increasing prevalence in aging populations. T2D, characterized by insulin resistance and defective insulin signaling, is a common co-morbidity and a risk factor for AD, increasing the risk approximately two to fourfold. Insulin exerts a wide variety of effects as a growth factor as well as by regulating glucose, fatty acid, and protein metabolism. Certain lifestyle factors, physical inactivity and typical Western diet (TWD) containing high fat and high sugar are strongly associated with insulin resistance and T2D. The PI3K-Akt signaling pathway is a major mediator of effects of insulin and plays a crucial role in T2D pathogenesis. Decreased levels of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) subunits as well as blunted Akt kinase phosphorylation have been observed in the AD brain, characterized by amyloid-beta and tau pathologies. Furthermore, AD mouse models fed with TWD have shown to display altered levels of PI3K subunits. How impaired insulin-PI3K-Akt signaling in peripheral tissues or in the central nervous system (CNS) affects the development or progression of AD is currently poorly understood. Interestingly, enhancement of PI3K-Akt signaling in the CNS by intranasal insulin (IN) treatment has been shown to improve memory in vivo in mice and in human trials. Insulin is known to augment neuronal growth and synapse formation through the PI3K-Akt signaling pathway. However, PI3K-Akt pathway mediates signaling related to different functions also in other cell types, like microglia and astrocytes. In this review, we will discuss the most prominent molecular mechanisms related to the PI3K-Akt pathway in AD and how T2D and altered insulin signaling may affect the pathogenesis of AD.
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