Molecular and cellular processes connecting type 2 diabetes to Alzheimer's disease, focusing on oxidative stress, metabolic dysfunction, and neurodegeneration.

Advancing age has been associated with an imbalance between a gradual increase in reactive oxygen species (ROS) production and a decline in the efficiency of antioxidant defense mechanisms. Due to the fact that organisms are constantly exposed to endogenous and exogenous ROS sources, this condition of oxidative stress promotes a systemic pro-oxidant state that, in conjunction with many other risk factors, progressively worsens throughout life, triggering the development of chronic diseases, such as type 2 diabetes (T2D) and Alzheimer's disease (AD). These diseases have emerged as closely interconnected conditions that share some common molecular and cellular mechanisms. In this review, on the light of literature data, we explore the interconnection between several pathological processes implicated in both diseases, focusing on a series of cellular and molecular alterations, from metabolic dysfunction to neurodegeneration (including insulin resistance, oxidative stress, mitochondrial and endoplasmic reticulum dysfunction, among others). We highlight how the connection between those processes may culminate in the development of neurodegeneration and disease progression. Furthermore, we discuss the challenges and limitations to model those diseases, emphasizing some aspects of the current knowledge in terms of providing new perspectives to the development of multi-target therapeutic approaches.