Abstract

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder in our society, as the population ages, its incidence is expected to increase in the coming decades. The etiopathology of this disease still remains largely unclear, probably because of the highly complex and multifactorial nature of AD. However, the presence of mitochondrial dysfunction has been broadly described in AD neurons and other cellular populations within the brain, in a wide variety of models and organisms, including post-mortem humans. Mitochondria are complex organelles that play a crucial role in a wide range of cellular processes, including bioenergetics. In fact, in mammals, including humans, the main source of cellular ATP is the oxidative phosphorylation (OXPHOS), a process that occurs in the mitochondrial electron transfer chain (ETC). The last enzyme of the ETC, and therefore the ulterior generator of ATP, is the ATP synthase. Interestingly, in mammalian cells, the ATP synthase can also degrade ATP under certain conditions (ATPase), which further illustrates the crucial role of this enzyme in the regulation of cellular bioenergetics and metabolism. In this collaborative review, we aim to summarize the knowledge of the presence of dysregulated ATP synthase, and of other components of mammalian mitochondrial bioenergetics, as an early event in AD. This dysregulation can act as a trigger of the dysfunction of the organelle, which is a clear component in the etiopathology of AD. Consequently, the pharmacological modulation of the ATP synthase could be a potential strategy to prevent mitochondrial dysfunction in AD.

Highlights

  • Alzheimer’s Disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia in the world

  • It is our humble opinion that further research should be conducted in this field to better validate mitochondrial bioenergetics in general, and the mammalian ATP synthase, as a pharmacological target to prevent the cellular dysfunctions present in AD

  • The authors of this study proposed that these findings do not contradict the bibliography suggesting a crucial role for reactive oxygen species (ROS) in the cellular damage observed in AD

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Summary

Introduction

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia in the world. Caucasian Americans [10,11] The causes for these differences in the incidence of AD in individuals from different genders, races, and ethnicities remain mostly unknown, even if it has been proposed that it could be tied to health disparities, such as those that increase the risk of cardiovascular disease, more than to specific mutations [10,11]. One of the most prevalent of these early features of AD is the presence of mitochondrial dysfunction in diverse cellular types, including astrocytes and neurons [32,33,34]. 2021, 22, 11185 of the most prevalent of these early features of AD is the presence of mitochondrial dys of 17 function in diverse cellular types, including astrocytes and neurons [32,33,34]. Dysfunction is anisearly, crucialcrucial component of cell death in AD

Mitochondrial
ATP Synthase Dysfunction in AD
Dysregulation of Other Complexes of the ETC in AD
Mitochondrial Calcium Homeostasis
Conclusions
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