Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease

Abstract

A growing body of evidence supports an intriguing clinical/epidemiological connection between Alzheimer disease (AD) and type 2 diabetes (T2D). T2D patients have significantly increased risk of developing AD and vice versa. Recent studies have begun to reveal common pathogenic mechanisms shared by AD and metabolic disorders, notably obesity and T2D. In T2D and obesity, low-grade chronic inflammation is a key mechanism leading to peripheral insulin resistance, which progressively causes tissue deterioration and overall health decline. In the brain, proinflammatory signaling was recently found to mediate impaired neuronal insulin signaling, synapse deterioration, and memory loss. Here, we review evidence indicating that inflammation, insulin resistance, and mitochondrial dysfunction are common features in AD and T2D. We further propose the hypothesis that dementia and its underlying neuronal dysfunction are exacerbated or driven by peripheral inflammation. Identification of central and peripheral inflammation as potential mediators of brain dysfunction in AD may lead to the development of effective treatments for this devastating disease.

Topical Administration of GLP-1 Receptor Agonists Prevents Retinal Neurodegeneration in Experimental Diabetes

“…It has been reported that GLP-1 and longer-lasting protease-resistant analogs cross the blood-brain barrier and exert a neuroprotective action in the brains of mouse models of several neurodegenerative diseases, such as Alzheimer disease (28,29). In this regard, several clinical trials (30,31) aimed at exploring the effects of GLP-1R agonists on preventing the development of Alzheimer disease are in progress.…”

Neuroinflammation: Peripheral and Neurogenic Underlying Processes

“…In turn, this increases the appetite and caloric intake by up-regulating the body weight homeostasis in the paraventricular nucleus of the hypothalamus, affecting also cardiovascular functions and blood pressure (de Kloet et al, 2014;Rui, 2013). Altogether, these settings promote neuron injury, resulting in the alteration of cognitive functions (Elias et al, 2003) and may favor neurodegenerative diseases like AD and PD (Bousquet et al, 2012;De Felice and Ferreira, 2014). How brain inflammation is initiated during both obesity and hypertension is a debatable issue, under continuous investigation.…”

Alzheimer’s Disease Therapeutic Approaches

“…Neuroinflammation along with the process of seeding and spread is initiated eventually with neuronal dysfunction, and toxicity ensue [89]. With the event of insulin resistance, defective insulin signaling, and also the mitochondrial dysfunction in the brain, which are the common quirk of T2DM and AD; hamming the questions which one leads the other in the aged people [90][91][92].…”