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.

The Role of Mitochondrial Dysfunction in Alzheimer’s: Molecular Defects and Mitophagy-Enhancing Approaches

“…In addition to previous categories, ROS contains both radical and non-radical ROS classes formed by an incomplete decrease in oxygen, such as hydroxyl radical (HO), superoxide hydrogen peroxide (H 2 O 2 ), radical anion (O 2 ), peroxynitrite (ONOO-), and nitric oxide (NO). As mentioned by other authors [31,34], the main site for the generation of OS is mitochondria through OXPHOS, in which electrons escape from the ETC in the mitochondrial cavity for generating the construction of O 2 . Moreover, protein nitrosylation/oxidation can also produce in methionine oxidation and S-nitrosylation (sulfoxidation), and the latter is the creation of the response between N 2 O 3 and cysteine moiety to produce an SNO (S-nitrosothiol) [25,32].…”

“…Assessing MDA amounts, which are both cheap and easy to gather, might be of abundant significance for observing the development of AD and, thus, avoiding or treating it [31,32]. Contrarily, the OS indices that are regularly applied in biological specimens comprise TBARS (thiobarbituric acid-reactive constituents), free fatty acid statements, 2-propen-1-al (acrolein), neuro and iso-prostane synthesis, and HNE (4-hydroxy-2-transnonenal) for LPO; 3-NT (3-nitrotyrosine) and protein carbonyls (PC) for protein oxidation; progressive glycation completion molecules for carbohydrates; and 8-hydroxydeoxyguanosine (8-OHdG), 8-hydroxy-2'-deoxyguanosine (8-OHdG), other oxidized sources, and changed DNA restoration machinery for RNA and DNA oxidation [31]. Recently, the augmentations levels of toxic carbonyls, such as HNE and 3-NT, are among the earliest modifications realized after instigating the OS affront in AD [33].…”

“…The transcript of NH 2 hTau in advanced hippocampal primary nerve cells changes mitochondria assembly, prompts synaptic changes, and augments mitophagic fluidity, as proven via administration with suppressors in cooperation with autophagosome synthesis with lysosomal and lysosome protein declination [64]. Mitophagy's genomic or pharmacological reticence also prohibited NH2hTau-intermediated damages [31,63]. Some of the above articles assumed that the aggregation of NH 2 hTau might contribute to synaptic damage in models of AD via aggravating mitophagy action.…”

Natural antioxidants that act against Alzheimer’s disease through modulation of the NRF2 pathway: a focus on their molecular mechanisms of action

“…Healthy mitochondria are critical organelles that are responsible for ATP production, metabolism, stress responses and maintaining protein homeostasis. In AD, the accumulation of high levels of Aβ and p-tau and the overexpression of tau are directly related to the generation of mitochondrial damage, as demonstrated by several recent studies ( 65 – 67 ). One of the important consequences of these processes is that they induce ROS generation causing excessive mitochondrial fragmentation and promoting defective mitophagy ( 68 , 69 ).…”