Brain Mitochondrial Dysfunction: A Possible Mechanism Links Early Life Anxiety to Alzheimer's Disease in Later Life

Abstract

Alzheimer's disease (AD) is usually manifested in patients with dementia, accompanied by anxiety and other mental symptoms. Emerging evidence from humans indicates that people who suffer from anxiety in their early life are more likely to develop AD in later life. Mitochondria, the prominent organelles of energy production in the brain, have crucial physiological significance for the brain, requiring considerable energy to maintain its normal physiological activities. Net reactive oxygen species (ROS) was produced by mitochondrial impairment, in which oxidative stress is also included, and the production of ROS is mostly more than that of removal. In this paper, we propose that as a critical process in brain pathology, mitochondrial dysfunction caused by anxiety triggering oxidative stress might be a possible mechanism that links early life anxiety to AD in later life. Several pivotal physiological roles of mitochondria are reviewed, including functions regulating glucose homeostasis, which may disrupt in oxidative stress. Increased levels of oxidative stress are constantly shown in anxiety disorder patients, and antioxidant drugs have promise in treating anxiety. In the early stages of AD, mitochondrial dysfunction is concentrated around senile plaques, a landmark lesion composed of aggregated Aβ and Tau protein. In turn, the accumulated Aβ and Tau disrupts mitochondrial activity, and the tricky physiological processes of mitochondria might be significant to the course of AD. In the end, we conclude that mitochondria might present as one of the novel therapeutic targets to block oxidative stress in patients with anxiety disorders to prevent AD in the early stage.

Keywords: Alzheimer’s disease; anxiety; early life; mitochondrial dysfunction; oxidative stress.

Figure 1.

Overview of the pathogenesis of AD triggered by extracellular and intravascular Aβ deposition. Step 1 shows the interaction of Aβ oligomers and fibronectin with neuronal cells through several receptors which in turn triggers an overall increase in brain Aβ levels. Step 2 shows that neurons suffer from impaired mitochondrial bioenergetics and glucose homeostasis and thus degeneration. Step 3 illustrates that the neuroinflammatory environment and oxidative stress to which the neuronal cells are exposed can exacerbate the pathological process of AD. In addition, the top right corner of the figure shows the anxiolytic drugs reported in the literature for the treatment of AD models, with the crosses on the left corresponding to the respective antipathogenic mechanism in the figure and the classification of the drug in parentheses. Abbreviations: Aβ, amyloid peptide; GLUT, glucose transporter; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; ROS, reactive oxygen species; PSD95, postsynaptic density protein-95.