Abstract
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-β 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.
Highlights
Both Alzheimer’s disease (AD) and type 2 diabetes (T2D) are diseases reaching epidemic proportions
Results from epidemiological, clinical, and animal model-based studies have already established a strong association between T2D and AD, and alteration in PI3K-Akt signaling is the common denominator in these diseases
Recent finding revealed that P50T genetic variation in AKT2 gene, which leads to insulin resistance and hyperinsulinemia in the periphery, increased the glucose uptake in the brain as assessed by [18F]-FDG PET imaging (Latva-Rasku et al, 2018)
Summary
Both Alzheimer’s disease (AD) and type 2 diabetes (T2D) are diseases reaching epidemic proportions. Type 2 diabetes is a complex, age- and lifestyle-related chronic disease It is characterized by increased glucose and insulin levels in the blood, insulin resistance, metabolic abnormalities, and chronic inflammation (Sjöholm and Nyström, 2006; Ashcroft and Rorsman, 2012). Imaging studies have shown that T2D is often associated with changes in the brain that are typically detected in patients with AD and related dementias, including decreased hippocampal volume, reduced glucose metabolism, and changes in cerebral blood flow (Baker et al, 2011; Moran et al, 2013; Willette et al, 2015). In a preclinical APP/PS1 AD mouse model, IN treatment led to the specific activation of the Akt isoform (Gabbouj et al, 2019) This suggests that Akt kinases may have isoform-specific roles in insulin signaling in the brain. The aim in this review article is to summarize and discuss the effects of altered insulin-PI3K-Akt signaling and T2D on the pathogenesis of AD
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