How Does Alzheimer's Affect The Nervous System – Neurons are highly specialized post-mitotic cells that are inherently dependent on mitochondria for their higher bioenergetic requirements. Mitochondrial dysfunction is closely associated with various age-related neurological disorders such as Alzheimer’s disease (AD), and the accumulation of dysfunctional and redundant mitochondria is considered an early stage that significantly facilitates the progression of AD. Mitochondrial damage leads to bioenergetic deficiency, intracellular calcium imbalance and oxidative stress, thereby exacerbating amyloid-β (Aβ) accumulation and tau hyperphosphorylation, as well as causing cognitive decline and memory loss. Although there is a complex parallel relationship between mitochondrial dysfunction and AD, their triggering factors, such as Aβ aggregation and hyperphosphorylated Tau protein, as well as the timing of action are still unclear. In addition, many studies have confirmed that abnormal mitochondrial biosynthesis, dynamics, and function occur following disruption of mitochondrial quality control, leading to exacerbation of pathological changes in AD. Accumulating evidence shows the beneficial effects of appropriate exercise in improving mitochondrial mitophagy and function, promoting mitochondrial plasticity, reducing oxidative stress, improving cognitive function, and reducing the risk of cognitive impairment and dementia later in life. Therefore, stimulating mitophagy and optimizing mitochondrial function through exercise may prevent the neurodegenerative process of AD.
As the aging population worsens, dementia has become the third leading cause of death after cancer and heart disease and is one of the most challenging illnesses for healthcare workers today. According to 2021 U.S. statistics, approximately 6.2 million Americans age 65 and older are living with Alzheimer’s dementia today; by 2060, this number could increase to 13.8 million (Alzheimer’s Association, 2021). Alzheimer’s disease (AD), a complex, multifactorial, heterogeneous neurodegenerative disease, is the most common form of dementia, characterized by progressive loss of memory and cognitive abilities. Although the incidence of AD continues to rise, there are currently no effective disease-modifying drugs for the treatment of AD.
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How Does Alzheimer's Affect The Nervous System
Currently, the pathogenesis of AD is not clearly understood, and the common features of the clinical diagnosis of AD are senile plaques (SP) and intraneuronal neurofibrillary tangles (NFTs), formed by extracellular deposits of amyloid β (Aβ) due to aggregated and hyperphosphorylated Tau proteins (Khan et al. ., 2020). Given the background, Hardy and Higgins first proposed the amyloid cascade hypothesis, which posits that Aβ protein aggregation is the initiator of pathological damage in AD. The above hypothesis suggests that Aβ deposition in the brain is the initial and central part of the pathological changes in AD (Hardy and Higgins, 1992), which induces several pathological processes such as Aβ plaques, tau phosphorylation, NFT and neuronal death. . These pathological processes increase Aβ deposition, thereby forming an amplification cascade and ultimately leading to cognitive decline (Liu et al., 2019). The amyloid cascade hypothesis has been considered a key pathogenic concept in AD research in recent decades. However, recent clinical studies based on the amyloid cascade hypothesis have been questioned by disappointing results (Sperling et al., 2011; Selfridge et al., 2013), and this hypothesis does not explain the pathological mechanisms of AD, but rather its combination with other hypotheses. may become a future trend in AD treatment research.
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Increasing evidence suggests that mitochondrial dysfunction is a major pathological factor in age-related neurodegenerative diseases (ND) ( Stanga et al., 2020 ; Johnson et al., 2021 ). It is worth noting that although bioenergetic defects and associated oxidative stress are the main cause of LBP, evidence of impairment in mitochondrial dynamics, biogenesis, and autophagy has recently suggested a causal relationship between altered mitochondrial function and LBP (Cabezas-Opazo et al., 2015). . . Therefore, to prevent diseases associated with mitochondrial dysfunction and cell death, a variety of mechanisms to maintain mitochondria in an appropriate functional state are required (Wu et al., 2019). In this case, targeting mitochondrial dysfunction may be a potential therapeutic strategy to delay or prevent the early neurodegenerative process of AD and attenuate neuronal death.
Aging is a major risk factor for the onset and progression of AD, and physical inactivity is considered an important contributor to increased morbidity and mortality in patients with AD (Norton et al., 2014). At the same time, exercise appears to strongly modulate mitochondrial metabolism in the brain. Exercise has been recognized as an ideal non-drug therapy for improving cognitive function, improving mitochondrial dysfunction, and effectively delaying and restoring cognitive functions such as memory in older adults (Cass, 2017; Luo et al., 2017; Zhao et al., 2021) . This article summarizes the oxidative stress, biogenesis, dynamics and mitophagy of mitochondria involved in the aging process, the relationship between AD caused by dysfunctional mitochondria and related physical exercise, and the underlying mechanisms of action of relevant factors influencing these processes.
A large body of experimental evidence indicates that late-stage fibrillar deposits of phosphorylated tau and Aβ accumulation are the hallmark neuropathological features of AD (Swerdlow, 2012). However, the changes that lead to Aβ accumulation and tau hyperphosphorylation in cellular homeostasis are unclear. In this case, several lines of evidence confirmed that plaque formation alone does not cause neurotoxicity. In addition to plaque and tangle deposition, mitochondrial function in Alzheimer’s disease brains may be seriously affected by other processes (Perez Ortiz and Sverdlov, 2019). According to previous literature reports, mitochondrial DNA (mtDNA) levels in neurons tend to decrease before the development of NFT (Mao and Reddy, 2011), and the activity of tricarboxylic acid (TCA) cycle enzymes is significantly reduced (Bubber et al). . al., 2005), accompanied by a decrease in glucose metabolism in the brain (Azari et al., 1993). Thus, Aβ and Tau pathology influences mitochondrial function of brain cells (Eckert et al., 2011), and dysfunctional or damaged mitochondria represent critical early neuropathological hallmarks of AD (Gibson and Shi, 2010).
Subsequently, Swerdlow and Han proposed the mitochondrial cascade hypothesis, in which genetic factors determine basic mitochondrial function in humans and environmental factors determine the rate of mitochondrial changes caused by aging ( Swerdlow and Han, 2004 ). Therefore, the accumulation of damaged mitochondria can cause both neuropathological changes and the corresponding symptoms of AD. According to this hypothesis, aging is a leading risk factor for the development of sporadic Alzheimer’s disease (SAD), and Aβ accumulation is a consequence of aging rather than a cause of neuropathological evolution (Swerdlow et al., 2010). This hypothesis is supported by SP formation from Aβ deposits, deficits in energy metabolism and increased oxidative stress ( Lejri et al., 2019 ), as well as mitochondrial morphology and function ( Oliver and Reddy, 2019 ; Pradeepkiran and Reddy, 2020 ). ), indicating that mitochondrial function may influence amyloid-β precursor protein (APP) formation and Aβ accumulation in AD. The mitochondrial cascade hypothesis is a complement to the amyloid cascade hypothesis, which suggests an important role for mitochondrial functional state in the production, modification and accumulation of Aβ and tau, as well as oligomer formation (Swerdlow, 2018). Moreover, another report also described mitochondrial dysfunction based on the accumulation of Aβ and pathogenic tau (Mossmann et al., 2014). The question of whether mitochondrial dysfunction can lead to AD or whether corresponding pathologies can subsequently lead to mitochondrial dysfunction is a widely debated topic. Thus, mitochondrial dysfunction may be an upstream inducer of Aβ and hyperphosphorylated tau, while Aβ and hyperphosphorylated tau may further exacerbate mitochondrial dysfunction, thereby causing a vicious circle response in AD (Figure 1).
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Figure 1. Mitochondrial cascade hypothesis and amyloid cascade hypothesis in AD. In unaffected neurons, intact mitochondria are distributed throughout the neuron. In Alzheimer’s disease neurons, mitochondrial dysfunction leads to insufficient energy metabolism and increased oxidative stress, leading to increased amyloidogenic APP processing and aggregation of hyperphosphorylated tau. Pathogenic Aβ and hyperphosphorylated tau can lead to impaired mitophagy, a subsequent increase in damaged or dysfunctional mitochondria, and blockade of mitolysosomes, leading to neuronal death in AD.
As essential cellular organelles, mitochondria play a dominant role in neurophysiological functions, thereby supporting cell survival through the integration of cellular respiration, energy metabolism, and calcium.
Balance. Under physiological conditions, the fusion of healthy and damaged mitochondria can dilute damaged materials into the healthy mitochondrial network, preventing the accumulation of dysfunctional mitochondria. After mitochondrial fission, dysfunctional or damaged portions of mitochondria are sequestered and finally cleared by mitochondrial phagocytosis, thereby effectively maintaining mitochondrial quantity and quality Youle and van der Bliek (2012). Since diseases associated with mitochondrial dysfunction were first discovered by (Luft et al., 1962), the role of mitochondria in health, disease and aging is now widely studied and confirmed. In this regard, a large body of evidence confirms that mitochondrial dysfunction is a causative factor in the development of AD. Based on the mitochondrial cascade hypothesis, aging directly accelerates mitochondrial damage in brain neurons, causes increased mitochondrial oxidative stress, impairs mitochondrial biogenesis, thereby causing an imbalance in mitochondrial dynamics, inhibiting mitophagy, impairing mitochondrial quality control. and worsening of pathological processes in blood pressure (Fig. 2).
Figure 2. Impaired mitochondrial function and mitophagy in AD. Older neurons exhibit decreased PGC-1α signaling for mitochondrial biogenesis, impaired mitochondrial fusion and fission, and inhibition of mitophagy flux, which promotes fragmentation.
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