1 Introduction

Alzheimer's Disease (AD), colloquially known as Alzheimer's, represents a relentless and irreversible neurodegenerative condition that primarily targets the brain, resulting in a gradual deterioration of cognitive abilities and memory. This pervasive form of dementia affects a vast population globally, numbering in the millions, and imposes a substantial weight on individuals, their families, as well as healthcare systems worldwide [1]. The symptoms of Alzheimer's are comprehensive and manifest in various ways, affecting multiple aspects of an individual's cognitive and functional abilities. Memory impairment is one of the earliest and most noticeable symptoms, with patients experiencing difficulties in recalling recent events or conversations. Over time, this memory loss progresses to include the inability to remember important details from the past, such as personal histories or significant life events. The etiology of Alzheimer's Disease remains unknown, and scientists continue to research the underlying causes and mechanisms of the disease [2]. However, two pathological hallmarks have been identified as characteristic of the disease: amyloid plaques and neurofibrillary tangles [3]. Amyloid plaques, which are aggregations of a protein named beta-amyloid, accumulate at the intersections of neuronal synapses, interrupting the transformation of messages between neurons. In contrast, neurofibrillary tangles are intricate entanglements of the tau protein that accumulate inside the neuronal cell bodies, impeding their regular operations and functions. By further investigating hallmarks and other chemical levels in AD patients, the pathogenesis of Alzheimer's Disease involves several hypotheses that attempt to explain the underlying mechanisms of the disease [4]. The cholinergic hypothesis suggests that AD arises from the death of neurons that release acetylcholine. The AB protein production and metabolic disorder hypothesis suggests that the excessive production and subsequent accumulation of beta-amyloid plaques within the brain disrupts normal intracellular chemical processes, ultimately contributing to the onset and progression of Alzheimer's disease (AD). The oxidative stress and free radical damage hypothesis posit that excessive oxidative stress damages cell membranes, causing neuronal death. While the cholinergic hypothesis, which postulates a central role for reduced ACh levels in AD, remains a significant theory, our research paper aims to delve deeper into the intricate interplay between this hypothesis and a diverse array of other theories that have garnered attention in the field. Our primary focus is not to reinforce the exclusivity of the cholinergic hypothesis but rather to meticulously examine how it intertwines with and informs these other hypotheses. By doing so, we aspire to shed light on the nuanced relationships between these theories and, specifically, to illuminate the intricate correlation between the cholinergic hypothesis and the pathogenesis of AD. [5]

2 Acetylcholine

2.1 Introduction to Acetylcholine

Acetylcholine, a vital neurotransmitter in the human body, plays a crucial role in various physiological processes, particularly those related to muscle contraction and cognitive functions [6]. This chemical messenger is intricately involved in the communication between neurons and muscle cells, as well as within the nervous system itself, where it facilitates memory formation and thought processes. At the neuromuscular junction, acetylcholine is secreted by alpha motor neurons to activate skeletal muscle cells, triggering their contraction. Beyond its role in muscle contraction, acetylcholine also serves as a key player in cognitive processes. Within the brain, neurons communicate through the release and reception of neurotransmitters, including acetylcholine. This chemical messenger plays a vital part in memory formation and retrieval, as well as in decision-making and problem-solving. If the levels of acetylcholine in neuron cells decline significantly, it can lead to the development of Alzheimer's disease. Research has shown that acetylcholine deficiency is closely linked to the disruption of neural circuits in the prefrontal cortex (PFC), a key brain region involved in short-term memory and learning. In AD patients, degeneration of basal forebrain cholinergic neurons, which innervate the PFC, results in reduced acetylcholine levels in this region. This cholinergic deficit is believed to contribute to the short-term memory impairment observed in AD. Studies using mouse models of AD have demonstrated that administering M1-type cholinergic receptor agonists in the PFC can effectively enhance cognitive function, highlighting the importance of acetylcholine in maintaining PFC integrity and function. Furthermore, recent research utilizing advanced imaging techniques has uncovered the intricate neural circuits involving acetylcholine that underlie short-term memory formation and retrieval in the context of AD. This current research highlights the promising prospects of employing therapeutic approaches that specifically target the cholinergic system, with the aim of mitigating cognitive decline among Alzheimer's disease patients [7].

2.2 The Cholinergic Hypothesis

The Cholinergic Hypothesis posits that a decline in the function of the cholinergic system, specifically the basal forebrain cholinergic neurons that produce and release the neurotransmitter acetylcholine, is a fundamental contributor to the cognitive decline observed in AD [8]. ACh is a critical molecule for the proper functioning of neural circuits involved in memory, attention, and other cognitive processes. In AD, the basal forebrain cholinergic neurons undergo significant degeneration, leading to reduced production and release of ACh in the brain. This reduction in ACh levels disrupts the normal functioning of neural circuits, particularly those in the prefrontal cortex and hippocampus, which are essential for memory formation and retrieval [9]. As a result, patients with AD experience progressive memory loss and cognitive impairment. The Cholinergic Hypothesis suggests that restoring or enhancing cholinergic neurotransmission, through the use of drugs that increase ACh levels or prevent its breakdown, could potentially alleviate some of the cognitive symptoms associated with AD [10]. In fact, several medications that target the cholinergic system, such as ACh esterase inhibitors, have been developed and are currently used to treat AD patients.

3 Factors contributing to acetylcholine nerve cell death

3.1 The oxidative stress and free radical damage hypothesis

The oxidative stress and free radical damage hypothesis is a widely accepted scientific theory that explains the underlying mechanisms of cellular damage and aging. The proposed theory asserts that an imbalance arises between the production of reactive oxygen species (ROS) and the body's ability to counteract or repair the detrimental effects of these species [11]. This imbalance leads to a condition referred to as oxidative stress, which subsequently results in cellular malfunction and eventual deterioration of tissues. This theory has been studied extensively in various fields, including biology, medicine, and nutrition, and has implications for understanding the development of numerous diseases and conditions. Reactive oxygen species, known as ROS, are highly reactive molecular byproducts that occur naturally within the body during various metabolic activities, such as breathing and cell signaling. Types of ROS include superoxide, hydrogen peroxide, and hydroxyl radicals, all of which possess potent reactivity. While small amounts of ROS are necessary for maintaining normal cellular functions, excessive levels can cause oxidative stress, leading to damage to DNA, proteins, and lipids. The body has several mechanisms in place to combat oxidative stress and prevent free radical damage. Antioxidants, for instance, are molecules that can neutralize ROS and prevent them from causing harm. Examples of antioxidants include vitamins C and E, glutathione, and carotenoids [12]. Moreover, essential enzymes like superoxide dismutase, catalase, and glutathione peroxidase play a vital part in neutralizing reactive oxygen species (ROS) and safeguarding cells from oxidative stress. However, oxidative stress arises when the generation of ROS overwhelms the body's capacity to counterbalance them, thereby leading to cellular damage. This can be caused by various factors, including exposure to environmental pollutants, smoking, excessive alcohol consumption, and poor nutrition. Oxidative stress can also occur because of aging, as the body's natural antioxidant defenses become less effective over time. The oxidative stress and free radical damage hypothesis have been implicated in the progression of numerous diseases and conditions. Multiple health conditions, including cardiovascular disorders, cancerous growths, diabetes, and various neurodegenerative ailments, notably Alzheimer's and Parkinson's diseases, have been found to be intimately tied to oxidative stress, highlighting its widespread role in the progression of these conditions. Additionally, oxidative stress has been proved to play a role in the aging process itself, contributing to the decline in cellular function and tissue integrity that occurs with age. To effectively counter oxidative stress and mitigate free radical damage, it is crucial to embrace a wholesome lifestyle characterized by a nutritious, balanced diet that is abundant in antioxidants, participating in daily physical activity, and refraining from detrimental substances like tobacco and superfluous alcohol consumption. Supplements containing antioxidants may also be beneficial for individuals who are at risk of oxidative stress, such as those with chronic diseases or who are undergoing treatment with medications that can increase ROS production.

3.2 Oxidative stress and acetylcholine nerve cell death

The intricate interplay between the cholinergic hypothesis and the factors contributing to acetylcholine nerve cell death, particularly oxidative stress, forms a pivotal aspect of our understanding of Alzheimer's disease. Oxidative stress, a condition marked by an unequal ratio of reactive oxygen species (ROS) generation and the body's antioxidant capabilities, has emerged as a critical factor in the deterioration of neurons in AD [13]. This imbalance, which arises from multiple sources within the brain, exerts a profound impact on cholinergic neurons, ultimately leading to their demise and contributing to the cognitive decline observed in AD patients. In the context of AD, oxidative stress arises from various sources, including dysfunctional mitochondria and neuroinflammation. Dysfunctional mitochondria, a hallmark of AD pathology, produce excessive amounts of ROS, overwhelming the antioxidant defense system and causing oxidative damage to cellular components [14]. This damage, which targets lipids, proteins, and DNA, disrupts normal cellular function and initiates a cascade of events leading to neuronal death. Neuroinflammation, another key feature of AD, further exacerbates oxidative stress by activating microglia and astrocytes, which release inflammatory mediators that can generate additional ROS [15]. Cholinergic neurons are particularly vulnerable to oxidative stress. In these neurons, oxidative stress disrupts the normal function of acetylcholine synthesis and transport, thereby reducing the availability of this important neurotransmitter. Acetylcholine, synthesized in the presynaptic terminal of cholinergic neurons, is essential for the proper functioning of neural circuits involved in memory and cognition. When oxidative stress impairs the synthesis and transport of acetylcholine, the resulting deficit in neurotransmission disrupts these circuits, contributing to the cognitive decline observed in AD. Moreover, ROS generated during oxidative stress can activate apoptotic pathways, leading to the programmed death of cholinergic neurons. One such pathway, the intrinsic mitochondrial pathway, is particularly relevant in the context of AD [16]. In this pathway, ROS damage the mitochondrial membrane, causing the release of cytochrome c into the cytosol. Cytochrome c, in turn, activates caspase cascades, a series of proteolytic enzymes that cleave cellular proteins, including those essential for cell survival. This cleavage ultimately results in the breakdown of the cell and its death by apoptosis. The activation of apoptotic pathways in cholinergic neurons is particularly concerning given their critical role in cognitive function. As cholinergic neurons degenerate, the loss of their neurotransmitter, acetylcholine, further disrupts neural circuits and exacerbates cognitive decline. This vicious cycle, in which oxidative stress leads to neuronal death and reduced neurotransmission, which in turn exacerbates oxidative stress, underscores the importance of understanding and addressing oxidative stress in AD.

3.3 The AB protein production and metabolic disorder hypothesis

The generation of Amyloid β protein and the subsequent metabolic disturbance hypothesis is a prominent theory in the field of AD research. This hypothesis suggests that the abnormal production and accumulation of Aβ in the brain, particularly in the form of protein plaques within nerve cells, are central to the pathogenesis of AD. Amyloid β is a proteolytic byproduct that arises from the enzymatic cleavage of the Amyloid Precursor Protein by β- and γ-secretases [17]. The accumulation of Aβ in the brain serves as a defining characteristic of Alzheimer's Disease, indicating the presence of the disorder [18]. In healthy brains, the production and clearance of Aβ are carefully balanced to ensure that Aβ levels remain low, preventing its accumulation to harmful levels. The clearance mechanisms involve both proteolytic degradation by enzymes and removal by specialized cells, such as microglia and astrocytes. However, in AD patients, this balance is disrupted, resulting in an excess accumulation of Aβ and the formation of Aβ plaques. The presence of Aβ plaques triggers a cascade of inflammatory and oxidative stress responses in the brain. Microglia, the innate immune cells residing within the brain, become activated in response to the plaques, releasing inflammatory cytokines and reactive oxygen species. This chronic inflammation leads to further damage to neurons and surrounding tissues, exacerbating the disease process. In addition, the accumulation of Aβ disrupts the normal function of mitochondria, which are the energy-producing organelles within cells. Mitochondrial dysfunction impairs energy production and increases oxidative stress, leading to neuronal cell death. The metabolic disturbance hypothesis suggests that the buildup of Aβ disrupts the typical metabolic functioning within the brain. This can lead to a range of metabolic abnormalities, including impaired glucose metabolism, altered lipid metabolism, and changes in energy production. These metabolic disturbances can further exacerbate the disease process by contributing to neuronal cell death and the progression of AD.

3.4 Amyloid β protein and acetylcholine nerve cell death

The investigation into the mechanisms underlying acetylcholine nerve cell death, particularly in the context of Alzheimer's disease, has revealed a complex interplay between various factors, with Aβ plaques emerging as a pivotal contributor. Aβ plaques, composed of aggregated β-amyloid protein fragments, are a hallmark pathological feature of AD, progressively accumulating in the brain over time [19]. These extracellular deposits exert their toxic effects on neurons through several distinct pathways, ultimately leading to the degeneration of cholinergic neurons and the depletion of acetylcholine, a crucial neurotransmitter for cognitive function [20]. Firstly, Aβ plaques significantly contribute to synaptic dysfunction, the fundamental process of neuronal communication. Specialized connections known as synapses play a crucial role in enabling the communication between neurons. These intricate junctions facilitate the transmission of both electrical impulses and chemical signals, which are fundamental to the processes of cognition, memory formation, and behavioral responses. However, the presence of Aβ plaques disrupts this delicate balance, interfering with the normal functioning of synapses. By impairing the efficiency of signal transmission, Aβ plaques lead to a decline in synaptic strength and plasticity, which are crucial for learning and memory. This synaptic dysfunction, in turn, impairs cognitive function, making it increasingly difficult for individuals with AD to perform daily tasks and retain new information. Moreover, the disruption of synaptic function caused by Aβ plaques has far-reaching consequences for neurotransmitter homeostasis. Cholinergic neurons, which rely heavily on acetylcholine for communication, are particularly vulnerable to these changes. However, reduced synaptic function leads to alterations in neurotransmitter levels, including decreased acetylcholine availability. This neurotransmitter imbalance further exacerbates cognitive decline, as the reduced levels of acetylcholine impair the ability of cholinergic neurons to effectively communicate with their targets. In addition to synaptic dysfunction and neurotransmitter imbalance, Aβ plaques also trigger a neuroinflammatory response in the brain. This inflammatory cascade is initially triggered by the presence of the plaques themselves, attracting immune cells such as microglia and astrocytes to the site of deposition. While this initial response is intended to clear the plaques and mitigate their toxic effects, chronic inflammation can have devastating consequences for neurons. Inflammatory molecules released by immune cells, including cytokines, chemokines, and reactive oxygen species, can damage neuronal structures and impair function. This neuroinflammatory response is particularly damaging to cholinergic neurons, as they are particularly sensitive to the cytotoxic effects of inflammatory molecules. The combination of synaptic dysfunction, neurotransmitter imbalance, and neuroinflammation creates a toxic environment for acetylcholine nerve cells, ultimately leading to their death. As cholinergic neurons degenerate, the levels of acetylcholine in the brain decrease further, exacerbating the cognitive decline observed in AD. The loss of these neurons and the corresponding reduction in acetylcholine levels are thought to be key drivers of the memory loss and cognitive impairment characteristic of the disease.

3.5 Tau hyperphosphorylation hypothesis

The Tau hyperphosphorylation hypothesis is a pivotal theory in the ongoing effort to understand the mechanisms underlying AD. This hypothesis proposes that the abnormal accumulation and hyperphosphorylation of the Tau protein, a crucial component of the neuronal cytoskeleton, plays a critical role in the pathogenesis of AD. Tau protein, in its normal state, functions to stabilize microtubules, which are essential for maintaining the structural integrity and function of neurons. However, in AD, Tau undergoes extensive post-translational modifications, including hyperphosphorylation, which leads to its detachment from microtubules and subsequent aggregation into neurotoxic structures known as neurofibrillary tangles (NFTs) [21]. These tangles disrupt neuronal function and ultimately contribute to the cognitive decline and neuronal loss that characterizes AD.

The Tau hyperphosphorylation hypothesis rests on several compelling evidences. Firstly, rigorous pathological examinations of brains affected by Alzheimer's Disease consistently uncover a substantial presence of neurofibrillary tangles. Secondly, genetic investigations have pinpointed mutations within the Tau gene that lead to early-onset familial AD, thereby reinforcing the connection between Tau and the pathogenesis of AD. Additionally, in vitro and in vivo studies have shown that hyperphosphorylated Tau is more prone to aggregation and exhibits neurotoxic properties, such as disrupting cellular homeostasis and impairing neuronal function. The mechanisms underlying Tau hyperphosphorylation in AD are complex and multifaceted. One of the key factors involved is the deregulation of kinases and phosphatases, which are enzymes that add and remove phosphate groups from proteins, respectively. In AD, the activity of certain kinases, such as glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (Cdk5), is upregulated, leading to increased Tau phosphorylation [22]. Conversely, the activity of phosphatases that remove phosphate groups from Tau is downregulated, contributing to the accumulation of hyperphosphorylated Tau. Furthermore, post-translational modifications (PTMs) of Tau, such as ubiquitination, acetylation, and glycosylation, can also influence its phosphorylation status. For example, ubiquitination of Tau can target it for degradation by the proteasome, reducing its overall levels and phosphorylation status. Conversely, acetylation of Tau can stabilize its conformation and promote its aggregation into NFTs. The Tau hyperphosphorylation hypothesis has crucial implications for the processing of AD therapies. By targeting the kinases and phosphatases involved in Tau phosphorylation, researchers aim to reduce the levels of hyperphosphorylated Tau and prevent the formation of NFTs. Additionally, drugs that modulate Tau PTMs may also have therapeutic potential, as they can influence the conformation and function of Tau, reducing its neurotoxicity.

3.6 Tau protein and acetylcholine nerve cell death

The intricate relationship between the formation of Tau tangles and the death of acetylcholine nerve cells poses a formidable obstacle in comprehending and managing Alzheimer's disease (AD). When the Tau protein abnormally folds and clumps together into tangles within nerve cells, it initiates a sequence of pathological processes that eventually culminate in neuronal death, especially affecting cholinergic neurons. In this section, we delve deeper into the mechanisms underlying the detrimental effects of Tau tangles on acetylcholine nerve cells, exploring their disruption of cytoskeletal structure, contribution to synaptic degeneration, and direct neurotoxicity, as well as their interplay with Aβ plaques. Tau protein, in its normal state, plays a vital role in stabilizing microtubules, which are essential for intracellular transport and maintaining the structural integrity of neurons. Microtubules serve as tracks for the movement of organelles, vesicles, and proteins within the neuron, enabling the efficient delivery of nutrients, enzymes, and signaling molecules to various compartments. However, when Tau misfolds and aggregates into tangles, it disrupts the microtubule network, impairing intracellular transport and leading to a decline in neuronal health and function. This disruption of the cytoskeletal structure has profound consequences for acetylcholine nerve cells. Without efficient intracellular transport, these neurons struggle to maintain their metabolic needs and signaling capabilities. As a result, they become more vulnerable to oxidative stress, excitotoxicity, and other insults that can trigger cell death. Furthermore, the impairment of intracellular transport disrupts the normal flow of neurotransmitters and neurotrophic factors, further compromising neuronal communication and survival. Synaptic degeneration is another critical consequence of Tau tangles on acetylcholine nerve cells. Synapses are the points of contact between neurons, where information is transmitted through the release and reception of neurotransmitters. In AD, Tau tangles can disrupt the normal functioning of synapses, leading to a decline in neuronal communication and ultimately contributing to cognitive impairment. Cholinergic neurons, which are particularly vulnerable in AD, rely heavily on their synaptic connections to maintain their function. As Tau tangles accumulate within these neurons, they disrupt the delicate balance of synaptic signaling, leading to the weakening of synapses and a decline in the overall functioning of the neuron. This synaptic degeneration further exacerbates the neurodegenerative process, creating a vicious cycle of neuronal decline and death. In addition to disrupting the cytoskeletal structure and contributing to synaptic degeneration, Tau tangles can also exert direct neurotoxicity on acetylcholine nerve cells. The accumulation of misfolded and aggregated Tau protein within neurons triggers a cascade of inflammatory and oxidative stress responses, which can lead to the destruction of cellular components and ultimately result in cell death. This neurotoxicity is particularly pronounced in cholinergic neurons, which are known to be more sensitive to oxidative stress and excitotoxicity. As Tau tangles accumulate within these neurons, they trigger the release of reactive oxygen species and other toxic molecules, which damage cellular membranes, DNA, and proteins. This damage, in turn, activates apoptotic pathways, leading to the programmed death of the neuron. The accumulation of Aβ plaques and Tau tangles in the brain does not occur in isolation; they often coexist and amplify each other's damaging effects. This interplay creates a vicious cycle that accelerates neuronal degeneration and death, particularly among acetylcholine nerve cells. Aβ plaques can promote the formation of Tau tangles by inducing oxidative stress and inflammatory responses, which disrupt the normal functioning of Tau protein and promote its misfolding and aggregation. Conversely, Tau tangles can also exacerbate the formation of Aβ plaques by disrupting neuronal function and promoting the accumulation of toxic amyloid precursor protein fragments. This interplay between Aβ plaques and Tau tangles creates a toxic environment within the brain, which is particularly harmful to cholinergic neurons. The combined effects of oxidative stress, inflammation, and synaptic degeneration lead to the rapid degeneration and death of these neurons, contributing to the cognitive decline and memory loss that characterize AD.

4 Conclusion

In conclusion, the mechanisms and factors contributing to acetylcholine nerve cell death in Alzheimer's disease (AD) are intricate and multifaceted, involving a complex interplay between genetic, molecular, and environmental factors. This research highlights critical pathways and hypotheses contributing to the degeneration of cholinergic neurons, resulting in cognitive decline and functional impairments in Alzheimer's disease patients.

The cholinergic hypothesis, which posits that the degeneration of cholinergic neurons releasing acetylcholine contributes to AD pathogenesis, remains a cornerstone of our understanding of the disease. Acetylcholine is intricately involved in the proper functioning of neural circuits in the prefrontal cortex and hippocampus. As cholinergic neurons undergo significant degeneration in AD, resulting in reduced levels of acetylcholine, the normal functioning of these circuits is disrupted, contributing to memory loss and cognitive impairment. The oxidative stress and free radical damage hypothesis has emerged as a significant contributor to acetylcholine nerve cell death in AD. This hypothesis contends that an excess of reactive oxygen species (ROS) compared to the body's antioxidant capabilities creates a state of oxidative stress, which triggers cellular malfunction and ultimately results in the deterioration of tissues. In the context of AD, oxidative stress arises from multiple sources, including dysfunctional mitochondria and neuroinflammation, overwhelming the antioxidant defense system and causing oxidative damage to cholinergic neurons. This damage disrupts the normal function of acetylcholine synthesis and transport, ultimately leading to neuronal death and exacerbating cognitive decline. The AB protein production and metabolic disorder hypothesis also plays a pivotal role in the pathogenesis of AD. The abnormal production and accumulation of Amyloid β protein in the brain, particularly in the form of plaques, disrupts synaptic function and neurotransmitter homeostasis, impairing cholinergic neuron communication. Moreover, Aβ plaques trigger a neuroinflammatory response, releasing inflammatory molecules that damage neuronal structures and impair function, particularly among cholinergic neurons. The combination of synaptic dysfunction, neurotransmitter imbalance, and neuroinflammation creates a toxic environment for acetylcholine nerve cells, leading to their degeneration and death. The Tau hyperphosphorylation hypothesis provides another important insight into the mechanisms underlying AD. The abnormal accumulation and hyperphosphorylation of the Tau protein disrupts the cytoskeletal structure and contributes to synaptic degeneration, directly affecting acetylcholine nerve cells. As Tau misfolds and aggregates into tangles, it disrupts the microtubule network, impairing intracellular transport and leading to oxidative stress, excitotoxicity, and cell death. Furthermore, Tau tangles can trigger inflammatory and oxidative stress responses, exacerbating the neurotoxic effects on cholinergic neurons. Importantly, the buildup of Aβ plaques and Tau tangles does not occur in isolation; they often coexist and amplify each other's damaging effects. This interplay creates a vicious cycle that accelerates neuronal degeneration and death, particularly among acetylcholine nerve cells. By disrupting synaptic function, neurotransmitter homeostasis, and neuronal communication, Aβ plaques and Tau tangles create a toxic environment within the brain, contributing to the rapid degeneration and death of cholinergic neurons.

Understanding the intricate interplay between these various factors and hypotheses is crucial for developing effective treatment strategies aimed at preserving neuronal function and improving patient outcomes. Therapeutic approaches that target the cholinergic system, reduce oxidative stress, mitigate neuroinflammation, and prevent Aβ and Tau accumulation hold great promise for alleviating the cognitive symptoms associated with AD. For example, medications that enhance cholinergic neurotransmission, such as ACh esterase inhibitors, have been developed and are currently used to treat AD patients. Similarly, antioxidants, anti-inflammatory agents, and drugs that target kinases and phosphatases involved in Tau phosphorylation may also have therapeutic potential.

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