Pathology, Risk Factors, and Oxidative Damage Related to Type 2 Diabetes-Mediated Alzheimer's Disease and the Rescuing Effects of the Potent Antioxidant Anthocyanin

Abstract

The pathology and neurodegeneration in type 2 diabetes- (T2D-) mediated Alzheimer's disease (AD) have been reported in several studies. Despite the lack of information regarding the basic underlying mechanisms involved in the development of T2D-mediated AD, some common features of the two conditions have been reported, such as brain atrophy, reduced cerebral glucose metabolism, and insulin resistance. T2D phenotypes such as glucose dyshomeostasis, insulin resistance, impaired insulin signaling, and systemic inflammatory cytokines have been shown to be involved in the progression of AD pathology by increasing amyloid-beta accumulation, tau hyperphosphorylation, and overall neuroinflammation. Similarly, oxidative stress, mitochondrial dysfunction, and the generation of advanced glycation end products (AGEs) and their receptor (RAGE) as a result of chronic hyperglycemia may serve as critical links between diabetes and AD. The natural dietary polyflavonoid anthocyanin enhances insulin sensitivity, attenuates insulin resistance at the level of the target tissues, inhibits free fatty acid oxidation, and abrogates the release of peripheral inflammatory cytokines in obese (prediabetic) individuals, which are responsible for insulin resistance, systemic hyperglycemia, systemic inflammation, brain metabolism dyshomeostasis, amyloid-beta accumulation, and neuroinflammatory responses. In this review, we have shown that obesity may induce T2D-mediated AD and assessed the recent therapeutic advances, especially the use of anthocyanin, against T2D-mediated AD pathology. Taken together, the findings of current studies may help elucidate a new approach for the prevention and treatment of T2D-mediated AD by using the polyflavonoid anthocyanin.

Figure 1

Obesity, free fatty acids, and insulin resistance. A diagrammatic representation showing the role of obesity in metabolic dysregulation via the release of inflammatory cytokines, oxidative stress, and lipotoxicity. Secretion of FFA and proinflammatory cytokines results in ROS/oxidative stress-mediated JNK activation. Inflammatory cytokines cause low-grade inflammation in peripheral organs and induce type 2 diabetes. Similarly, chronic FFA treatment induces insulin resistance and beta-cell dysfunction and causes type 2 diabetes. ROS: reactive oxygen species; RNS: reactive nitrosative stress; FFA: free fatty acid; ER: endoplasmic reticulum.

Figure 2

Rich sources of anthocyanins. Fruits and vegetables rich in the polyflavonoid anthocyanin.

Figure 3

Dysbiosis, leaky gut, inflammatory cytokines, and insulin resistance. A simple illustration showing the release of lipopolysaccharides (LPS) and disruption of tight junctions in the intestinal wall resulting in the release of inflammatory cytokines, which enter the blood and pancreatic beta-cells. In addition, the TLR4 receptors in LPS play a role in the release of microglial cells. The reactive microglial cells secrete inflammatory cytokines and cause insulin resistance. NF-κB: nuclear factor-kappa B; TNF-α: tissue necrosis factor-alpha; TLR4: Toll-like receptor 4.

Figure 4

Shared links between Alzheimer's disease and diabetes. A simple illustration showing the shared links between Alzheimer's disease and diabetes.

Figure 5

Insulin resistance, oxidative stress, and Aβ pathology. Downregulation of Akt and perturbation of the activities of the IDE lead to aggregation of amyloid-beta plaques and hyperphosphorylation of tau protein. On the other hand, chronic hyperglycemia directly promotes oxidative stress and neuroinflammation and causes neurodegeneration. Aβ = amyloid-beta; IDE = insulin-degrading enzyme; GSK3β = glycogen synthase kinase 3 beta.

Figure 6

The effects of sedentary lifestyle, obesity, alcohol consumption, and mental distress on insulin sensitivity, induction of inflammation, release of free fatty acids, oxidative stress, hyperglycemia, neuronal insulin resistance, and AD pathology. T2DM = type 2 diabetes mellitus; Aβ = amyloid-beta; FFA = free fatty acid; BBB = blood-brain barrier.