Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

Abstract

Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in the elderly population worldwide. A growing body of epidemiological studies suggest that people with T2DM are at a higher risk of developing AD. Likewise, AD brains are less capable of glucose uptake from the surroundings resembling a condition of brain insulin resistance. Pathologically AD is characterized by extracellular plaques of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau. T2DM, on the other hand is a metabolic disorder characterized by hyperglycemia and insulin resistance. In this review we have discussed how Insulin resistance in T2DM directly exacerbates Aβ and tau pathologies and elucidated the pathophysiological traits of synaptic dysfunction, inflammation, and autophagic impairments that are common to both diseases and indirectly impact Aβ and tau functions in the neurons. Elucidation of the underlying pathways that connect these two diseases will be immensely valuable for designing novel drug targets for Alzheimer's disease.

Keywords: abeta oligomers; autophagy; inflammation; insulin resistance; synaptic dysfunction; tau proteins.

Figure 1

Overview of the diverse mechanisms by which Type 2 Diabetes can cause AD pathogenesis. Type 2 Diabetes accompanied by insulin resistance and hyperglycemia gives rise to metabolic problems in the brain and other target tissues that sets off a cascade of pathogenic processes such as oxidative stress, inflammatory responses, advanced glycation products and autophagic dysfunction. The reactive oxygen species generated by these pathways expedite the process of neuronal death. At the same time, the insulin resistance impairs the downstream signaling pathways and exacerbates the formation of Aβ oligomers and aggregates of hyperphosphorylated tau. The cumulative effect of all these factors expose the neurons to a range of assaults and gradually result in the loss of synapses and neuronal death.

Figure 2

Neuronal signaling mechanisms in a state of insulin sensitivity and insulin resistance. In the insulin sensitive state insulin binds to the receptor and activates the insulin receptor tyrosine kinase that initiates a cascade of phosphorylation events at the IRS/PI3K/AKT and Ras/Raf/ERK pathways. AKT phosphorylates GSK-3β at the inhibitory serine 9 residue and allows tau to maintain its physiological function of binding to microtubules and facilitates normal axonal transport of neuronal vesicles. In a state of insulin resistance, GSK-3β is activated by phosphorylation at Tyrosine 216 residue and hyperphosphorylates tau at pathological epitopes. Hyperphosphorylated tau then detaches from the microtubules and aggregates to form neurofibrillary tangles. Likewise, in the presence of excess insulin, the insulin degrading enzyme (IDE) is unable to degrade and facilitate clearance of Aβ oligomers that act as a competitive substrate for insulin. Thus, insulin resistance facilitates the formation of both Aβ and tau oligomers.

Figure 3

Insulin signaling also controls mTOR pathway that inhibits autophagy. Both insulin resistance in Type 2 Diabetes and Alzheimer's disease impairs the formation of autophagosomes and disrupts lysosomal function. Autophagosomes fuse with lysosomes to form autolysosomes. These autolysosomes have impaired lysosomal function in AD and T2DM and accumulate Aβ and tau aggregates. Undigested toxic aggregates are secreted out of the neurons and propagate toxic oligomers in adjacent neurons.