ATP Synthase and Mitochondrial Bioenergetics Dysfunction in Alzheimer's Disease

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.

Keywords: ATP synthase; ATPase; Alzheimer’s disease; OXPHOS; mitochondria; mitochondrial dysfunction.

Figure 1

Mitochondrial dysfunction is an early, crucial component of cell death in AD. Dysregulated OXPHOS, including the dysfunction of the ATP synthase, induces decreased ATP production and increased ROS. This will ultimately lead to a rise in the rates of apoptotic cell death not only in neurons but also in other cell types in the central nervous center. The increased death of cells will induce serious damage in the brains of the patients, which correlates with the symptoms of the disease. Interestingly, mitochondrial dysfunction, including dysregulated OXPHOS, is an early event in AD, preceding the accumulation of Aβ and the presence of NTFs. ↑ upregulated; ↓ downregulated.

Figure 2

Mitochondrial dysfunction is present at different levels in mitochondria, in a deleterious cycle which increases the damage to the organelle and the cells in AD. Dysregulation of the mitochondrial ATP synthase is present in neurons and other cellular populations in the brains of AD patients. This dysregulation will further contribute towards bioenergetics dysfunction and the consequent increased production of ROS. That rise in the levels of ROS is one of the main causes underlying the damage present in AD in the mtDNA, which will further affect the expression and the activity of the ATP synthase, starting the deleterious cycle again.