Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal

Abstract

Recently researchers proposed the term 'Type-3-Diabetes' for Alzheimer's disease (ad) because of the shared molecular and cellular features among Type-1-Diabetes, Type-2-Diabetes and insulin resistance associated with memory deficits and cognitive decline in elderly individuals. Recent clinical and basic studies on patients with diabetes and AD revealed previously unreported cellular and pathological among diabetes, insulin resistance and AD. These studies are also strengthened by various basic biological studies that decipher the effects of insulin in the pathology of AD through cellular and molecular mechanisms. For instance, insulin is involved in the activation of glycogen synthase kinase 3β, which in turn causes phosphorylation of tau, which involved in the formation of neurofibrillary tangles. Interestingly, insulin also plays a crucial role in the formation amyloid plaques. In this review, we discussed significant shared mechanisms between AD and diabetes and we also provided therapeutic avenues for diabetes and AD. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

Keywords: Alzheimer's disease; BMI; GSK3β; MCI amyloid beta; Obesity; Tau; Type-3-Diabetes; diabetes.

Figure 1

Schematic representation of T2DM/insulin resistance in Alzheimer’s disease through a) mitochondrial dysfunction, which in turn causes synaptic damage, and neuronal death, b) glycosylated hemoglobin in impaired cognitive function by failure in the transport of glucose for neurons, c) oxidative stress-induced amyloid beta and phosphorylated tau formations through advanced glycation end products , d) inflammation by mitochondrial dysfunction and toxicities of amyloid beta and glycation end products, e) activation of voltage-dependent anion channel by amyloid beta-induction in neuronal loss.

Figure 2

Insulin resistance in T2DM causes mitochondrial dysfunction, which in turn triggers inflammation response through either APP/hIAPP catabolism. Amyloid beta oligomers activate microglia in the production of cytokines. An orchestrated action triggered by stress kinases promotes both the inhibition of brain insulin signaling and elevated eIF2a–P. While both events act to promote insulin resistance and metabolic deregulation in diabetes, they are likely to contribute to synapse loss and impaired long-term potentiation.

Figure 3

Insulin resistance decreases glucose metabolism and plays a pivotal role in mitochondrial damage, DNA damage and ROS formation. This triplet action is involved in the formation of plaques.

Figure 4

Brief Illustration of insulin signaling pathway in a) healthy brain and b) AD brain. (Figure concept adapted from “Trends Neurosci. 2016 Jun 17. pii: S0166-2236(16)30037-6. “)

Figure 5

Role of amyloid beta oligomers on toxic effects of synapses, including synaptic degeneration, abnormal neurotransmitter release and cytoskeletal damage. Synaptotoxic effects cause defective axonal transport, mitochondrial fragmentation, degradation of kinases activity, oxidative stress, impaired LTP, increase in intracellular calcium levels.

Figure 6

Illustration of hypothalamus in the brain plays a crucial role in energy homeostasis by regulating two opposing neuronal axes, namely orexigenic axis and anorexigenic axis