Insulin dysfunction and Tau pathology

Abstract

The neuropathological hallmarks of Alzheimer's disease (AD) include senile plaques of β-amyloid (Aβ) peptides (a cleavage product of the Amyloid Precursor Protein, or APP) and neurofibrillary tangles (NFT) of hyperphosphorylated Tau protein assembled in paired helical filaments (PHF). NFT pathology is important since it correlates with the degree of cognitive impairment in AD. Only a small proportion of AD is due to genetic variants, whereas the large majority of cases (~99%) is late onset and sporadic in origin. The cause of sporadic AD is likely to be multifactorial, with external factors interacting with biological or genetic susceptibilities to accelerate the manifestation of the disease. Insulin dysfunction, manifested by diabetes mellitus (DM) might be such factor, as there is extensive data from epidemiological studies suggesting that DM is associated with an increased relative risk for AD. Type 1 diabetes (T1DM) and type 2 diabetes (T2DM) are known to affect multiple cognitive functions in patients. In this context, understanding the effects of diabetes on Tau pathogenesis is important since Tau pathology show a strong relationship to dementia in AD, and to memory loss in normal aging and mild cognitive impairment. Here, we reviewed preclinical studies that link insulin dysfunction to Tau protein pathogenesis, one of the major pathological hallmarks of AD. We found more than 30 studies reporting Tau phosphorylation in a mouse or rat model of insulin dysfunction. We also payed attention to potential sources of artifacts, such as hypothermia and anesthesia, that were demonstrated to results in Tau hyperphosphorylation and could major confounding experimental factors. We found that very few studies reported the temperature of the animals, and only a handful did not use anesthesia. Overall, most published studies showed that insulin dysfunction can promote Tau hyperphosphorylation and pathology, both directly and indirectly, through hypothermia.

Keywords: Alzheimer's disease; Tau phosphorylation; diabetes mellitus; kinases; phosphatases.

Figure 1

Insulin dysfunction might enhance Alzheimer's disease pathology through distinct mechanisms. Insulin dysfunction, manifested by either T1DM, characterized by insulin deficiency; or T2DM, characterized by insulin resistance, might lead to Tau phosphorylation and NFT formation, one of the major histopathological hallmarks of Alzheimer's disease. This effect can be induced either directly, through kinases activation (such as GSK-3β) and/or phosphatases inhibition (such as PP2A); or indirectly, through the effect of hypothermia on kinases and phosphatases activities. For note, insulin resistance might be related to Tau pathology through several mechanisms, mainly including inflammation and stress. Abbreviations: T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus; GSK-3β: glycogen synthase kinase 3β; PP2A: protein phosphatase 2A; NFT: neurofibrillary tangles.