Mechanism involved in insulin resistance via accumulation of β-amyloid and neurofibrillary tangles: link between type 2 diabetes and Alzheimer’s disease

Abstract

The pathophysiological link between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) has been suggested in several reports. Few findings suggest that T2DM has strong link in the development process of AD, and the complete mechanism is yet to be revealed. Formation of amyloid plaques (APs) and neurofibrillary tangles (NFTs) are two central hallmarks in the AD. APs are the dense composites of β-amyloid protein (Aβ) which accumulates around the nerve cells. Moreover, NFTs are the twisted fibers containing hyperphosphorylated tau proteins present in certain residues of Aβ that build up inside the brain cells. Certain factors contribute to the aetiogenesis of AD by regulating insulin signaling pathway in the brain and accelerating the formation of neurotoxic Aβ and NFTs via various mechanisms, including GSK3β, JNK, CamKII, CDK5, CK1, MARK4, PLK2, Syk, DYRK1A, PPP, and P70S6K. Progression to AD could be influenced by insulin signaling pathway that is affected due to T2DM. Interestingly, NFTs and APs lead to the impairment of several crucial cascades, such as synaptogenesis, neurotrophy, and apoptosis, which are regulated by insulin, cholesterol, and glucose metabolism. The investigation of the molecular cascades through insulin functions in brain contributes to probe and perceive progressions of diabetes to AD. This review elaborates the molecular insights that would help to further understand the potential mechanisms linking T2DM and AD.

CDK5: Key Regulator of Apoptosis and Cell Survival

“…CDK5 has also been identified to play important roles in processes such as cell death and proliferation, angiogenesis, migration of epithelial and cancer cells, inflammation, myogenesis, glucose metabolism, and insulin secretion in non-neuronal cells [53,87,[89][90][91][92]. These studies have investigated CDK5 function in cells such as cells of hematopoietic lineage, HEK293, COS7, MEF, HCT116, HeLa, adipoctyes, pancreatic β cells, and many other non-neuronal cell types [53,91].…”

“…Ubeda et al observed that elevated extracellular glucose concentration results in increased expression of p35 and a correlative increase in CDK5 kinase activity [93]. CDK5/p35 is able to stimulate the insulin promoter in response to elevated glucose levels as inhibition of CDK5 prevents stimulation of the insulin promoter [89,93]. Additionally, suppression of CDK5 and p39 results in inhibition of Ca 2+ -induced insulin exocytosis in pancreatic β cells [94].…”

The Interplay between Diabetes and Alzheimer’s Disease—In the Hunt for Biomarkers

“…Many scientists analyzed the effect of glucose or insulin on intracellular or extracellular Aβ levels [10,27,28]. An in vitro study showed that in primary neuronal cultures and in neuroN2a cells overexpressing the β chain of APP, insulin reduces the intracellular accumulation of Aβ by initiating the transport of APP/Aβ from the Golgi apparatus into the cell membrane.…”

Links Between Adiponectin and Dementia: From Risk Factors to Pathophysiology

“…Extracellular Aβ-amyloid deposition into oligomers, fibrils, and plaques is a major hallmark of AD pathological mechanism. It may cause the dysfunction of several crucial processes, such as synaptogenesis, neurotrophy, and apoptosis, showing neurotoxin in the disruption of learning and memory (Rad et al, 2018). Then, the amyloid cascade hypothesis is the most prevailing hypothesis and propose that Aβ accumulation is the initiating mechanistic event.…”

“…Studies have posed that insulin modulates various steps in the amyloid cascade, affecting Aβ aggregation in the brain. The disturbance of insulin signaling may inhibit Aβ clearance and accelerate the formation of neurotoxic Aβ plaque (Kim and Feldman, 2015;Rad et al, 2018). In addition, there is no doubt about the relevance of neuroinflammation in AD.…”