Diabetes–Alzheimer's Disease Link: Targeting Mitochondrial Dysfunction and Redox Imbalance

Abstract

Significance: It is of common sense that the world population is aging and life expectancy is increasing. However, as the population ages, there is also an exponential risk to live into the ages where the brain-related frailties and neurodegenerative diseases develop. Hand in hand with those events, the world is witnessing a major upsurge in diabetes diagnostics. Remarkably, all of this seems to be narrowly related, and clinical and research communities highlight for the upcoming threat that it will represent for the present and future generations. Recent Advances: It is of utmost importance to clarify the influence of diabetes-related metabolic features on brain health and the mechanisms underlying the increased likelihood of developing neurodegenerative diseases, in particular Alzheimer's disease. Thereupon, a wealth of evidence suggests that mitochondria and associated oxidative stress are at the root of the link between diabetes and co-occurring disorders in the brain. Critical Issues: The scientific community has been challenged with constant failures of clinical trials raising major issues in the advance of the therapeutic field to fight chronic diseases epidemics. Thus, a change of paradigms is urgently needed. Future Directions: It has become urgent to identify new and solid candidates able to clinically reproduce the positive outcomes obtained in preclinical studies. On this basis, strategies settled to counteract diabetes-induced neurodegeneration encompassing mitochondrial dysfunction, redox status imbalance, and/or insulin dysregulation seem worth to follow. Hopefully, ongoing innovative research based on reliable experimental tools will soon bring the desired answers allowing pharmaceutical industry to apply such knowledge to human medicine. Antioxid. Redox Signal. 00, 000-000.

The brain as an insulin-sensitive metabolic organ

“…In addition, insulin-resistant rodents have increased ROS production and impaired mitochondrial oxygen consumption in the brain, resulting in reduced ATP production and mitochondrial dyshomeostasis [ 115 , [169] , [170] , [171] ]. These effects are also observed in AD models, where excess ROS and disruptions to both mitochondrial function and quality control are prominent aspects of the disease [ 172 , 173 ].…”

The Role of Mitochondrial Quality Control in Cognitive Dysfunction in Diabetes

“…Mitochondria are also a major source and target of intracellular reactive oxygen species (ROS). Multiple studies have shown that mitochondrial dysfunction may be a key player in diabetes-associated brain alterations contributing to neurodegenerative events [24][25][26]. In the insulin resistant brain, the structural and functional damage of brain mitochondria was observed, including reduced mitochondrial electron transport chain (mETC) activity, decreased mitochondrial respiration and massive production of ROS [27][28][29][30].…”

Redox signaling and Alzheimer’s disease: from pathomechanism insights to biomarker discovery and therapy strategy

“…The global burden of neurological diseases has increased substantially during 1990-2015 due to ageing and expanding population numbers [2] and all clinical trials between 1984 and 2017 have failed to provide any improvement in clinical outcomes [3], suggesting mechanism-based therapies are pressingly needed. Hyperphosphorylated tau protein [4], β-amyloid (Aβ) aggregation [5], aging [6], and importantly, inflammation [7] and oxidative stress [8] are tightly implicated in AD neurodegeneration. Cellular stresses or normal metabolic processes continuously generate reactive oxygen species (ROS) and a basal level of oxidative stress is of great significance to cell survival, while severe oxidative stress inevitably results in widespread oxidative damage [9].…”