Type 2 Diabetes Mellitus and Alzheimer's Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets

Abstract

The global prevalence of diabetes mellitus and Alzheimer's disease is increasing alarmingly with the aging of the population. Numerous epidemiological data suggest that there is a strong association between type 2 diabetes and an increased risk of dementia. These diseases are both degenerative and progressive and share common risk factors. The amyloid cascade plays a key role in the pathophysiology of Alzheimer's disease. The accumulation of amyloid beta peptides gradually leads to the hyperphosphorylation of tau proteins, which then form neurofibrillary tangles, resulting in neurodegeneration and cerebral atrophy. In Alzheimer's disease, apart from these processes, the alteration of glucose metabolism and insulin signaling in the brain seems to induce early neuronal loss and the impairment of synaptic plasticity, years before the clinical manifestation of the disease. The large amount of evidence on the existence of insulin resistance in the brain during Alzheimer's disease has led to the description of this disease as "type 3 diabetes". Available animal models have been valuable in the understanding of the relationships between type 2 diabetes and Alzheimer's disease, but to date, the mechanistical links are poorly understood. In this non-exhaustive review, we describe the main molecular mechanisms that may link these two diseases, with an emphasis on impaired insulin and IGF-1 signaling. We also focus on GSK3β and DYRK1A, markers of Alzheimer's disease, which are also closely associated with pancreatic β-cell dysfunction and type 2 diabetes, and thus may represent common therapeutic targets for both diseases.

Keywords: Alzheimer’s disease; Aβ peptide; DYRK1A; diabetes; glycogen synthase kinase 3; insulin deficiency; insulin resistance; insulin secretion; tau.

Figure 1

Defective insulin signaling as a major molecular mechanism linking T2D and AD. The pathophysiology of T2D implicates peripheral insulin resistance, leading to decreased glucose uptake by skeletal muscles and adipose tissue and increased hepatic glucose production (HGP). Because insulin is a key neurotrophic and neuroprotective factor, brain insulin resistance would contribute to the pathogenesis of AD. Conversely, the neurodegeneration that occurs in the hypothalamus leads to the impaired regulation of peripheral metabolism and defective insulin secretion by pancreatic β cells.

Figure 2

DYRK1A and GSK3β enzymes: potential molecular actors implicated in pancreatic β-cell loss and neurodegeneration. Under physiological conditions, insulin inhibits GSK3β activity by phosphorylating it via the PI3K/Akt pathway. In the case of insulin resistance, GSK3β remains dephosphorylated and constitutively active, resulting in the hyperphosphorylation of tau. The aberrant activation of DYRK1A and GSK3β in the brain increases Aβ peptide production and causes the hyperphosphorylation of tau, resulting in the formation of amyloid plaques and neurofibrillary tangles, respectively. These aggregates cause neurodegeneration and induce the alteration of brain insulin signaling. In the endocrine pancreas, both DYRK1A and GSK3β inhibit β-cell proliferation, and GSK3β is associated with the inflammation of the islets of Langerhans. This leads to β-cell loss and insulin secretion deficiency, further aggravating the impaired insulin signaling in the brain.