Role of Autophagy in Postischemic Brain Neurodegeneration: History
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Subjects: Neurosciences
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After cerebral ischemia, autophagy was found to be activated in neuronal, glial and vascular cells. Some studies have shown the protective properties of autophagy in postischemic brain, while other studies have shown completely opposite properties. Thus, autophagy is now presented as a double-edged sword with possible therapeutic potential in brain ischemia. 

  • brain ischemia
  • autophagy
  • neurodegeneration

1. Epidemiology of Brain Ischemia

Ischemic brain injury in humans develops as a result of a sudden partial or complete occlusion of the cerebrovascular network supplying blood to the brain [1]. Brain ischemia can occur in individuals with immature and mature brains. Perinatal ischemic stroke occurs between the 20th week of pregnancy and the 28th day after birth [2,3]. The incidence of perinatal stroke is 29 per 100,000 live births per year [2,3,4,5]. Despite current therapies, at least 1 in 10 children after the first ischemic stroke have a recurrence in the next 5 years [2]. The annual direct cost of stroke in children in the US, counting inpatient and outpatient services, is approximately USD 1,000,000 [2]. Perinatal ischemic brain injury is not only the leading cause of mortality in the early days of life, but also neonates who survive and develop neurological disabilities, cognitive deficits and behavioral impairments that often last a lifetime, such as in the form of dementia [3].
It is estimated that ischemic focal brain injury in adults, which accounts for roughly 85–90% of all cases, is the dominant cause of progressive and irreversible disability in humans and the second cause of death [6,7,8,9,10,11,12,13,14]. The incidence of ischemic brain alterations increases with age in developed and developing countries, with the exception of China and India, where the incidence of brain ischemia has increased sharply in people under 40 years of age [15]. As of 2015, focal ischemic brain injury is the leading cause of death and disability in China, posing a very serious threat to the health of the country’s citizens [16]. According to China’s official brain ischemia program, it was estimated that 17.8 million Chinese citizens had a stroke in 2020, of which 3.4 million had a first-ever stroke and another 2.3 million died from a stroke [16]. In addition, roughly 12.5% of stroke survivors remain disabled for life, equivalent to 2.2 million stroke-associated disabilities in 2020 [16]. It was calculated that the cost of hospitalization due to stroke in 2020 was CNY 58.0 billion, of which patients paid CNY 19.8 billion [16]. These figures are staggering considering that China makes up only 18% of the world’s population [17]. In fact, stroke incidence and mortality in China are 28% and 35% higher than the global average, respectively [17]. In addition, China’s estimated lifetime risk of stroke is 39.3% for people aged 25 and over, significantly higher than the global average of 24.9% [17].
A meta-analysis of papers on ischemic stroke in India showed that in 18 analyzed papers in five studies, the age of patients was below 40 years [18]. The age range of the patients was between 32 and 67 years, with a mean of 54 ± 9 [18]. In the study, 64% was men [18]. Countries such as India estimate that approximately 14% of global disability-adjusted life years have been lost due to stroke [19]. It has been documented that 50–70% of stroke survivors regain independence, but 15–30% are permanently disabled and 20% require institutional care, including 3 months after the onset of the stroke [19]. This worrying trend shows that the rate of stroke among people aged 20 to 54 worldwide has increased from 13% in 1990 to 19% in 2016 [20,21]. In the 21st century, the number of cases of ischemic stroke in young adults has increased to approximately two million per year [22].
It should be emphasized that, currently, 70% of ischemic strokes and 87% of related deaths and irreversible disabilities predominant occur in poor countries [23]. In poor countries, the number of cases of ischemic stroke has more than doubled over the last forty years, occurring approximately 15 years earlier and causing more deaths than in developed countries [23,24]. Approximately 84% of stroke case patients in poor countries die within three years, compared with only 16% in developed countries [23]. Currently, it is estimated that there are approximately 15 million cases of ischemic stroke annually, of which approximately half die within a year [1,6,7,9,10,11,14]. It is also known that the number of postischemic patients across the world has reached approximately 33 million [10]. Due to aging in the European community, it is estimated that by 2025, the incidence of stroke in this group is likely to increase to 1.5 million [22]. The number of stroke survivors in the European Union is estimated to increase by 27% by 2047 due to an aging society and higher survival rates of the population [25].
Over the past 25 years, there has been a decrease in the death rate of ischemic stroke survivors around the world, despite an increase in the number of cases as a result of increased life expectancy [12]. In rich countries, cerebral ischemia occurs 10 times more often than hemorrhagic stroke, while in poor countries, the advantage is definitely smaller [12]. The risk of stroke recurrence after a first ischemic stroke in the first month of treatment has been shown to be high, at 1 in 25 [12]. The data indicate that individuals who have had a stroke have a high chance of having another stroke in the first year of approximately 10% and annually in subsequent years of approximately 5% [26]. Symptoms usually depend on the extent of ischemia and the region of the brain involved, and include sensory and motor disturbances that are generally permanent. Over 30–50% of people who have experienced cerebral ischemia are functionally dependent on other people [8]. One year after a stroke, 10% to 15% of survivors require assistance in a specialist facility [27]. Epidemiological studies indicate that the incidence of stroke in middle-aged people, i.e., 50–70 years old, is higher compared to people over 70 years old [28]. Stroke patients aged >85 years account for 17% of all cases, and in this age group, stroke is more common in women than in men [2]. On the other hand, older patients show a marked decline in overall performance between 6 and 30 months poststroke [29]. According to recent projections, by 2030, the number of stroke survivors is predicted increase to 77 million [10,30,31]. Despite this, the global death rate due to cerebral ischemia has decreased significantly [12]. If these global stroke trends continue, by 2030 there is predicted to be approximately 70 million stroke cases, approximately 12 million deaths and more than 200 million disability-adjusted life years annually [30,31]. Despite significant progress in the diagnosis and treatment of brain ischemia, it is assumed that around 2050, the number of brain ischemia cases is likely to double, and disability after stroke is predicted to also increase due to the increasing number of patients whom are likely to survive an ischemic episode [32,33].

2. Medical, Financial and Social Burdens of Brain Ischemia

Therefore, it is no surprise that the socioeconomic impact of stroke worldwide is massive and growing over time; for example, the annual cost in the European Union was EUR 38 billion in 2012, EUR 45 billion in 2015 and EUR 60 billion in 2017 [34]. In addition, the additional cost of treating people with postischemic dementia and other dementias is estimated to increase from USD 321 billion in 2022 to nearly USD 1 trillion by 2050 [35]. On top of this, patients suffering from poststroke dementia are more likely to develop various complications and numerous chronic diseases, which could certainly generate an even greater financial burden related to the treatment of comorbidities; hence, brain ischemia has become a global health problem [36]. Finally, human ischemic stroke is associated with a very low cure rate, negligible full recovery, frequent recurrence, permanent disability and high mortality [37].

3. Postischemic Neurodegeneration

Cerebral ischemia has been found to trigger a sequence of pathological events that can last from minutes to the remaining years of life [8,38,39,40,41]. These pathologies include energy failure, oxidative stress, excitotoxicity, neuroinflammation, cortical and subcortical infarcts, white matter rarefaction, blood–brain barrier damage, microbleeding and cerebral amyloid angiopathy [8,14,30,31,42,43,44,45]. The consequence of the above changes is additional hypoperfusion, causing the ischemia of the adjacent areas, gliosis, the accumulation of amyloid plaques and neurofibrillary tangles, neuronal death and, ultimately, brain atrophy [38,39,41,46,47,48,49]. A focal ischemic episode typically damages the brain cortex, hippocampus, temporal lobe, entorhinal cortex, amygdala and parahippocampus to varying degrees. Postischemia, these structures are involved in cognitive and memory deficits, and their progressive degeneration also induces behavioral changes. Cognitive impairment due to ischemia is mild to severe, and has been seen in approximately 35–70% of survivors one year after a stroke [50,51,52,53,54,55]. It should be noted, however, that it is common for cognitive function to fail to return to before stroke levels [55,56,57,58]. Dementia has been shown to occur even in cases with transient cognitive impairment after ischemia [55,59]. Studies show that cerebral ischemia accelerates the onset of dementia by approximately 10 years [60]. It is estimated that 8–13% of patients develop dementia immediately after a first stroke, and over 40% after a second stroke [10,54,60]. The estimated progression of dementia in patients who survive 25 years after a stroke is approximately 48% [46,60].
It is believed that one in six people in the world are likely to suffer a brain ischemia in their lifetime [1]. This is accompanied by massive neuronal death in vulnerable brain regions. Thus, understanding the molecular mechanisms of neuronal death arising from different forms of ischemic insults is a major goal of investigators in the field. Thus far, three pathways of ischemic neuronal cell death, such as necrotic, apoptotic and autophagocytotic, have been identified. Postischemic brain neurodegeneration, such as that seen in Alzheimer’s disease, is a progressive neurodegenerative disease with two progressive pathological changes, i.e., extracellular amyloid plaques composed of β-amyloid peptide and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. At present, there are no sufficient therapeutic strategies available. As there are currently no neuroprotective substances known to exist, neuroprotective molecular mechanisms have not been explained to this day. In contrast to necrosis and apoptosis, autophagy could possibly serve as a potential therapeutic target against ischemia–reperfusion brain injury [61].
Over the past two decades, it has been proposed that ischemic neuronal death is associated with folding molecules, such as amyloid and tau protein. Postischemia is characterized by progressive memory loss and cognitive impairment, which, finally, ends in full-blown dementia with the Alzheimer’s disease phenotype. Given the facts presented, postischemic therapy strategies should probably focus on two characteristic changes: pathogenic misfolded amyloid and tau protein with the hope of affecting macroautophagy, also called autophagy.

4. Autophagy as Hope after an Ischemic Episode

There are three types of autophagy in mammalian cells: macroautophagy, microautophagy and chaperon-mediated autophagy. Macroautophagy is the best-studied type and a widely recognized autophagy in mammalian cells [61,62,63,64,65,66,67,68,69,70]. The process of the development of macroautophagy, hereinafter referred to as “autophagy”, consists of a series of successive stages [67,69,70]. The first is the creation of a phagophore. After autophagy-inducing signals appear, a small liposome-like membrane structure forms somewhere in the cytoplasm. The membrane then continues to expand to form a flat lipid bilayer called the phagophore, which is a form of direct evidence in the initiation of autophagy. In the second stage, the autophagosome is formed. To this end, the phagophore is constantly stretched to incorporate various components and, finally, transforms into a spherical double-membrane structure, namely, the autophagosome [61,67,69,70], which randomly or selectively captures misfolded proteins or damaged organelles, for example, misfolded tau protein or amyloid [62,69,70]. Regarding autophagosomal membrane elongation, various ATG vesicles and ubiquitin-like binding systems are involved in this phenomenon [67,69,70]. Autophagosomes then fuse with lysosomes to form autophagolysosomes [67,69,70]. Finally, the autophagy cargo is broken down by lysosomal enzymes and the recovered nutrients, including amino acids, fatty acids, etc., are transported back into the cytoplasm as part of the recycling mechanism, while residues are excreted from the cell to the outside. Recently, autophagy has been shown to involve a wide range of signal regulation pathways, which have mainly been divided into the mammalian target of rapamycin-dependent and the mammalian target of rapamycin-independent pathways, creating a sophisticated and intricate network of signals that regulate autophagy either positively or negatively [61,67,69,70].
It has been widely accepted that autophagy is the self-defense of the cellular catabolic pathway through which some long-lived or misfolded proteins and damaged organelles are broken down into metabolic substances and recycled to maintain cellular homeostasis [62,67,69,70]. During the process of autophagy, dysfunctional and unnecessary proteins and cellular elements are surrounded with a double-membrane vesicle called the autophagosome and, next, the autophagosome fuses with the lysosome, which, ultimately, leads to the recycling and degradation of redundant intracellular structures and proteins [62,67,69,70]. Autophagy is very important for cell and tissue homeostasis and is actively involved in the aging process, as well as in many human and animal diseases, including neurodegenerative diseases such as Alzheimer’s disease or postischemic neurodegeneration [62,63,64,65,66,67,68,69,70].
In experimental cerebral ischemia, autophagy has been shown to have a protective effect through the inhibition of neuronal apoptosis [71,72,73]. It has been shown that autophagy can be a double-edged sword in damage after cerebral ischemia; hence, it can be destructive or protective [61]. Thus, if the protective effects of autophagy can be controlled, autophagy can be a valuable therapeutic target, but if it cannot be controlled, it can be a messenger of death. It seems that the induction of autophagy could become a potential therapeutic strategy in the treatment of various diseases, including postischemic neurodegeneration. On the other hand, some scientists suggest that the overinduction of autophagy can lead to cell death, so-called autophagy cell death, emphasizing that the induction of autophagy in the treatment of diseases is not without complications. Further research on this topic is required to avoid such problems. Researchers believe that there is likely to be a flexible adaptive capacity in different cells that face endogenous and exogenous stress. In a physiological situation, autophagy is activated after stress and helps cells survive by controlling the reuse and removal of dangerous intracellular cargo. In the above situation, autophagy causes a number of repair phenomena in the cells and even leads to the achievement of internal homeostasis by the cells, which results in a normal state. In contrast, if autophagy is impaired by pathogens and autophagy gene mutations, the adaptive capacity of cells decreases and cells are more susceptible to stress. On the other hand, if prolonged stress results in excessive or prolonged autophagy that exceeds the adaptive capacity of the cell, the overinduction of autophagy may trigger necrosis and apoptosis, ultimately, leading to cell death. Thus, autophagy appears to be a double-edged sword in the phenomenon of cellular adaptive machinery [74]. Whether autophagy is beneficial or harmful is determined by the rate of autophagy induction and the duration of its activation [67]. However, the role of autophagy in these processes is completely unclear and information about it in the literature is very limited. However, many different factors influence the occurrence and progression of cerebral ischemia. Although a great challenge has been undertaken to better understand postischemic brain neurodegeneration, some questions remain unanswered. Over the past two decades, increasing evidence has accumulated showing that autophagy is involved in the development of cerebral ischemic sequelae. To understand the contradictory findings presented above, it is important to pay attention to the level of autophagy, as too high or too low a level of activity can be harmful. The identification of the pathways that affect the balanced autophagy system could be of key importance in the development of therapies for diseases of the nervous system, including the postischemic neurodegeneration of Alzheimer’s disease proteinopathy.

This entry is adapted from the peer-reviewed paper 10.3390/ijms241813793

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