Altered Insulin Signaling in Alzheimer’s Disease Brain – Special Emphasis on PI3K-Akt Pathway

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.

Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

“…In the context of AD, the loss of sphingosine kinase 2 activity and SP1 production are key pathogenic drivers of Aβ-mediated neurodegeneration [36]. Another upregulated pathway of interest is PI3K-AKT signaling, which has been extensively implicated in the pathogenesis of AD given its crucial role mediating insulin effects in the brain and other functions in microglia and astrocytes [37]. Collectively, our results from the network analysis support STAT3 as an important transcriptional regulator in AD.…”

“…This is not surprising since protein kinases in this pathway regulate many cellular activities including cellular differentiation, proliferation, apoptosis, inflammation, and innate immunity [45]. In AD, the crosstalk between insulin and MAPK signaling pathways may play a role in the disease pathogenesis [37,46]. Similar pathways crosstalk may be involved in the pathogenesis of FTD.…”

The Synaptic Vesicle Protein 2a Interacts With Key Pathogenic Factors in Alzheimer’s Disease: Implications for Treatment

“…5D). Decreased levels of PI3K subunits, as well as blunted AKT kinase phosphorylation, have been observed in the brain of AD patients [64]. Insulin-like growth factor-2 (IGF-2) was reported to attenuates memory decline and amyloid plaques plaque formation in AD mouse model by activating the PI3K/AKT/CREB signaling pathway [65]., and insulin has been observed to promote neuron growth and synapse formation through the PI3K signal pathway [64,66].…”

Identification of functionally connected multi-omic biomarkers for Alzheimer’s Disease using modularity-constrained Lasso

“…Two recent studies have found a significant 247 correlation between peripheral insulin resistance and brain Aβ levels as measured by 248 Pittsburgh compound B-positron emission tomography (PiB-PET) [42,43]. The impaired 249 insulin-PI3K-Akt signaling observed in the AD brain has led to clinical trials studying 250 whether the enhancement of this pathway using intranasal insulin (IN) treatment is 251 beneficial [44]. Other enriched pathways that are previously reported with a key role in 252 AD include Focal adhesion [45], Ras signaling pathway [46], ECM-receptor interaction [47], 253 MAPK signaling pathway [48], Rap1 signaling pathway [49], etc.…”

“…Compared to individual mutations, genes or proteins identified using 42 traditional methods, such connected pattern can help improve not only the reliability of 43 identified biomarkers, but also their replicability and interpretability. 44…”