What Is Alzheimer's Disease How Does It Affect Someone – Neurons are specialized postmitotic cells that depend on mitochondria for their major bioenergetic needs. Mitochondrial dysfunction is closely related to various neurological disorders associated with aging, such as Alzheimer’s disease (AD), and the accumulation of dysfunctional and dysfunctional mitochondria has been described as an early stage of making the progression of AD easier. Mitochondrial damage causes bioenergetic deficiency, intracellular calcium deficiency, and oxidative stress, thereby increasing the accumulation of β-amyloid (Aβ) and Tau hyperphosphorylation, and further leads to senescence and memory loss. Although there is a complex relationship between mitochondrial dysfunction and AD, their causes such as Aβ aggregation and hyperphosphorylated Tau protein and the time of action are still unclear. In addition, many studies have confirmed that mitochondrial biosynthesis is impaired, energy, and function when mitochondrial quality control is impaired, resulting in pathological changes in AD. Evidence is accumulating to show the beneficial effects of appropriate exercise and improved mitophagy and mitochondrial function to promote mitochondrial plasticity, reduce oxidative stress, improve cognitive ability, and reduce the risk of mental retardation and disability in life. the future. Therefore, promoting mitophagy and promoting mitochondrial function through exercise may prevent the neurodegenerative process of AD.
With the aging of people, dementia has become the third killer of cancer and heart disease, and one of the most difficult diseases for health professionals today. According to statistics from the United States, as of 2021, approximately 6.2 million Americans aged 65 and older are living with Alzheimer’s dementia today; This number could grow to 13.8 million by 2060 (Alzheimer’s Association, 2021). Alzheimer’s disease (AD), a complex, multifactorial, heterogeneous neurodegenerative disorder, is a type of dementia that often results in progressive loss of memory and cognitive abilities. Although the incidence of AD continues to rise, there are currently no effective disease-modifying drugs to treat AD.
What Is Alzheimer's Disease How Does It Affect Someone
At present, the pathogenesis of AD is not clearly defined, but the most common features for AD clinical diagnosis are senile plaques (SP) from extracellular deposits of β-amyloid (Aβ) and intraneuronal neurofibrillary tangles. tangles (NFT) due to aggregation and hyperphosphorylated Tau. protein (Khan et al., 2020). By background, Hardy and Higgins first proposed the amyloid cascade hypothesis that Aβ protein accumulation is the cause of disease damage during the AD process. The above hypothesis believes that the accumulation of Aβ in the brain is the first and central link in the changes of AD (Hardy and Higgins, 1992), resulting in clinical processes such as Aβ plaques, Tau phosphorylation, NFTs and neuronal death. . . The treatment of these diseases increases the concentration of Aβ, causing an increase in the cascade and ultimately leading to a decrease in cognitive ability (Liu et al., 2019). The amyloid cascade hypothesis has been recognized as a key factor in AD studies over the past few decades. However, recent clinical studies based on the amyloid cascade hypothesis have been challenged by disappointing results (Sperling et al., 2011; Selfridge et al., 2013), and this hypothesis recently describes the pathological process of AD, but rather its combination. and other ideas. perhaps future practice in AD treatment research.
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Increasing evidence suggests that impairment of mitochondrial function is a major cause of age-related neurodegenerative diseases (ND) (Stanga et al., 2020; Johnson et al., 2021). It should be noted that although bioenergetic defects and related oxidative stress are the main causes of NB, evidence of impairment of mitochondrial dynamics, biogenesis and autophagy has recently shown a causal link between changes in mitochondrial function and NB (Cabezas-Opazo et al. , 2015). Therefore, several mechanisms to maintain mitochondria in a proper working condition are necessary to prevent diseases related to mitochondrial dysfunction and cell death (Wu et al., 2019). In this context, correcting mitochondrial dysfunction may be a therapeutic strategy that can delay or prevent the early neurodegenerative process of AD and reduce neuronal death.
Aging is a major risk factor for the development and progression of AD, and physical inactivity is recognized as an important factor contributing to increased morbidity and mortality in AD patients (Norton et al., 2014). . Meanwhile, mitochondrial metabolism in the brain seems to be improved by exercise. Exercise has been reported as a good non-pharmacological treatment for improving cognitive ability, improving mitochondrial dysfunction, delaying and rescuing poor brain functions such as memory in the elderly (Cass, 2017; Luo et al. ., 2017; Zhao et al. ., 2021). This article summarizes the oxidative stress, biogenesis, energy and mitophagy of mitochondria involved in the aging process, the link between AD due to dysfunctional mitochondria and important physical activity, and the processes in ‘under which important factors affect these processes.
A large body of experimental evidence suggests that late-stage fibrillar deposits of phosphorylated Tau and aggregated Aβ represent the neuropathological hallmarks of AD (Swerdlow, 2012). However, the changes in cellular homeostasis to cause the accumulation of Aβ and hyperphosphorylated Tau are unclear. In this context, a large body of evidence suggests that simple plaque development alone does not cause neurotoxicity. In addition to documentation and tangles, other processes can affect mitochondrial function in AD brain (Perez Ortiz and Swerdlow, 2019). According to previous reports, the level of mitochondrial DNA (mtDNA) in neurons provides a process that decreases before the formation of NFT (Mao and Reddy, 2011), and the activity of enzymes of tricarboxylic acid (TCA) is greatly reduced. (Bubber et al., 2005), which is accompanied by a decrease in glucose metabolism in the brain (Azari et al., 1993). Thus, the mitochondrial function of the brain is affected by Aβ and Tau pathology (Eckert et al., 2011), and dysfunctional or damaged mitochondria represent early neuropathological signs of AD (Gibson and Shi, 2010) .
Later, Swerdlow and Khan proposed the mitochondrial cascade hypothesis, that genes determine the basal mitochondrial function of individuals, and the rate of mitochondrial turnover in old age is determined by the environment. habitat (Swerdlow and Khan, 2004). Thus, the accumulation of damaged mitochondria may lead to neuropathic changes and symptoms consistent with AD. In terms of this theory, aging represents the main risk factor for the development of sporadic AD (SAD), and Aβ accumulation is the cause of aging rather than the cause of neuropathological development (Swerdlow et al., 2010). This hypothesis is supported by the formation of SP due to Aβ deposits, energy damage and increased oxidative stress (Lejri et al., 2019), as well as abnormal mitochondrial morphology and function (Oliver and Reddy, 2019; Pradeepkiran and Reddy, 2020). ). ), suggesting that mitochondrial function may influence amyloid β precursor protein (APP) and Aβ accumulation in AD. The concept of the mitochondrial cascade is a support for the concept of the amyloid cascade, which points to the important role of the functional state of the mitochondria in the production, modification and aggregation of Aβ and Tau and the formation of oligomers (Swerdlow, 2018). In addition, another report also described the accumulation of mitochondrial dysfunction caused by Aβ and pathogenic Tau (Mossmann et al., 2014). The topic of whether mitochondrial dysfunction can cause AD or whether underlying pathologies can eventually cause mitochondrial dysfunction is a hotly debated topic. Therefore, mitochondrial dysfunction may be the precursor of Aβ and hyperphosphorylated Tau, while Aβ and hyperphosphorylated Tau may worsen mitochondrial dysfunction, resulting in adverse reactions in AD (Figure 1).
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Figure 1. Mitochondrial cascade hypothesis and amyloid cascade hypothesis in AD. In unaffected neurons, healthy mitochondria are distributed throughout the neuron. In AD-related neurons, mitochondrial dysfunction leads to impaired metabolism and increased oxidative stress, leading to increased amyloidogenic processing of APP and accumulation of hyperphosphorylated Tau. Pathogenic Aβ and hyperphosphorylated Tau can cause abnormal mitophagy, resulting in an increase in damaged or dysfunctional mitochondria and mitolysosome inhibition, leading to muscle death in AD.
As a critical cellular organelle, mitochondria play a major role in neurophysiological functions, thus supporting cell life by coordinating cellular respiration, energy metabolism, and Ca.
Balance. Under physiological conditions, the mixture of healthy and damaged mitochondria can break down the damaged elements into a healthy mitochondrial network to prevent the accumulation of dysfunctional mitochondria. After mitochondrial fission, the inactive or damaged part of the mitochondria is isolated and then eliminated by mitochondrial phagocytosis, maintaining the mitochondrial number and quality Youle and van der Bliek (2012). Since diseases related to mitochondrial dysfunction were first discovered (Luft et al., 1962), the role of mitochondria in health, disease, and aging has been well studied and accepted. In this regard, many data support that mitochondrial dysfunction is a factor in the development of AD. According to the theory of the mitochondrial cascade, aging increases mitochondrial damage in the brain, triggers an increase in mitochondrial oxidative stress, reduces mitochondrial biogenesis, thereby leading to a lack of mitochondrial dynamics, and -inhibits mitophagy, disrupts the mitochondrial quality of disease control, worsens. of AD (Figure 2).
Figure 2. Impairment of mitochondrial function and mitophagy in AD. Aged neurons express negative PGC-1α signaling for mitochondrial biogenesis, mitochondrial fusion and fission are abnormal, and arrest mitophagic flux, promoting fragmentation.
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