Recent Development in the Understanding of Molecular and Cellular Mechanisms Underlying the Etiopathogenesis of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood–brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aβ on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials.

Putative Molecular Mechanisms Underpinning the Inverse Roles of Mitochondrial Respiration and Heme Function in Lung Cancer and Alzheimer’s Disease

“…A and APP are present within mitochondrial membranes, interacting with mitochondrial proteins, thereby amplifying ROS generation. This process leads to structural and functional impairment within the mitochondria, disrupting normal neural function [ 26 , 45 ]. Multiple molecular mechanisms have been suggested in AD [ 42 , 46 , 47 , 48 ].…”

“…Oxidative stress rises gradually in aging brains, leading to mtDNA mutations [ 134 ]. Oxidative stress has the potential to trigger tau phosphorylation and aggregation, as well as increase the construction and accumulation of A [ 26 , 135 ]. The accumulation of mtDNA mutations disrupts OXPHOS and an imbalance in antioxidant enzyme expression results in excessive ROS production during aging [ 135 ].…”

“…They also play a critical role in the process of cell death [ 25 ]. Some studies have reported mitochondrial dysfunction in AD and cancer [ 1 , 16 , 26 , 27 , 28 ]. The moderate generation of reactive oxygen species (ROS) by mitochondria in cancer cells contributes to cancer cell growth and proliferation [ 1 , 29 ].…”

“…They also disrupt OXPHOS, resulting in energy depletion in AD [ 28 ]. Studies have reported dysregulated heme metabolism, and elevated levels of free heme (or iron) in the brain in AD [ 26 , 35 , 36 ]. The accumulation of iron in the brain might promote neurodegeneration through oxidative damage in AD [ 37 , 38 ].…”

“…The accumulation of iron in the brain might promote neurodegeneration through oxidative damage in AD [ 37 , 38 ]. In AD patients, excessive iron in the inferior temporal cortex may hasten cognitive decline [ 26 , 39 ]. Furthermore, heme binds to amyloid beta (A ), creating complexes with increased peroxidase and superoxide activities, which further exacerbate oxidative stress [ 26 , 35 , 36 ].…”