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0INFLUENCE OF BETA-AMYLOID PLAQUES IN ALZHEIMER'S DISEASE
ELGUJA TSITLIDZE
Faculty of Natural Sciences and Health Care of Batumi Shota Rustaveli State University
Batumi, Georgia
Abstract. Alzheimer's disease (AD) is the most common form of dementia in the elderly, characterized by cognitive decline and memory loss. Central to its pathogenesis is the accumulation of beta-amyloid (Afi) peptides, which form plaques in the brain, disrupt neuronal function, and contribute to neurodegeneration. Early-onset familial Alzheimer's disease (FAD) is linked to gene variants in APP, PSEN1, or PSEN2, leading to increased production of toxic amyloid beta peptides that accumulate as plaques, resulting in neuronal death and progressive symptoms.
The human APP gene was identified in 1987 using partial protein sequence information from fi-amyloid. An increase in cognitive impairments among the aging population poses significant challenges for families and healthcare systems. Understanding the mechanisms of dementia's pathogenesis is crucial for developing effective preventive and therapeutic strategies, particularly as the prevalence of dementia continues to rise with an aging population.
Keywords: Alzheimer's disease (AD), Beta-amyloid (Afi), APP, Neuronal death, Genotyping Analysis.
Introduction
Alzheimer's disease (AD) is the most prevalent form of dementia among the elderly, marked by cognitive decline and memory loss. Central to its pathogenesis is the accumulation of beta-amyloid (AP) peptides, which form plaques in the brain, disrupt neuronal function, and contribute to neurodegeneration. This review examines the multifaceted roles of AP in AD, particularly focusing on its metabolism, the influence of apolipoprotein E (ApoE), and the implications for cognitive decline and other types of dementia.
APP Processing and its Role in Alzheimer's Disease
The Global action plan on the public health response to dementia 2017-2025 aims to improve the lives of people with dementia, their carers and families, while decreasing the impact of dementia on communities and countries. It provides a set of actions to realize the vision of a world in which dementia is prevented and people with dementia and their carers receive the care and support they need to live a life with meaning and dignity. [2], [3]. '
Some cases of early-onset Alzheimer's disease are caused by gene variants (also called mutations) that can be passed from parent to child.
This results in what is known as early-onset familial Alzheimer's disease (FAD). Researchers have found that this form of the disorder can result from variants in the APP, PSEN1, or PSEN2 genes. When any of these genes is altered, large amounts of a toxic protein fragment called amyloid beta peptide are produced in the brain. This peptide can build up in the brain to form clumps called amyloid plaques, which are characteristic of Alzheimer's disease. A buildup of toxic amyloid beta peptide and amyloid plaques may lead to the death of nerve cells and the progressive signs and symptoms of this disorder. Other cases of early-onset Alzheimer's disease may be associated with changes in different genes, some of which have not been identified. [6], [7]. [8]. [9].
The human APP gene was first identified in 1987 using partial protein sequence information from purified P-amyloid (AP) to identify the corresponding cDNA (Kang et al. 1987). Amyloid-beta precursor protein is an ancient and highly conserved protein. [4], [5]. [10]. [11].
The P-amyloid precursor protein (APP) is primarily known for its role in producing P-amyloid (AP) associated with Alzheimer's disease. [12], [15]. [16]. [17].
Some cases of early-onset Alzheimer's disease are caused by gene variants (also called mutations) that can be passed from parent to child. This results in what is known as early-onset
familial Alzheimer's disease (FAD). Researchers have found that this form of the disorder can result from variants in the APP, PSEN1, or PSEN2 genes.
When any of these genes is altered, large amounts of a toxic protein fragment called amyloid beta peptide are produced in the brain. This peptide can build up in the brain to form clumps called amyloid plaques, which are characteristic of Alzheimer's disease.
A buildup of toxic amyloid beta peptide and amyloid plaques may lead to the death of nerve cells and the progressive signs and symptoms of this disorder. Other cases of early-onset Alzheimer's disease may be associated with changes in different genes, some of which have not been identified. The APP gene provides instructions for making a protein called amyloid precursor protein.
This protein is found in many tissues and organs, including the brain and spinal cord (central nervous system). Little is known about the function of amyloid precursor protein.
Researchers speculate that it may bind to other proteins on the surface of cells or help cells attach to one another. Studies suggest that in the brain, it helps direct the movement (migration) of nerve cells (neurons) during early development.
However, its normal functions are less understood. Research suggests that APP may have trophic functions, including promoting neural stem cell development, neuronal survival, neurite outgrowth, and neurorepair. Evidence indicates that APP interacts with various intracellular and extracellular signaling pathways, although the exact mechanisms of its actions are still to be determined.
After APP is produced, it undergoes modifications like glycosylation and phosphorylation. It then moves to the cell surface and is internalized via endocytosis into the endosomal-lysosomal system, where most of it is degraded.
APP is processed by secretases:
• a-Secretase: Cleaves APP, producing soluble fragments (sAPPa) and leaving behind
C83.
• P-Secretase (BACE1): Cleaves APP to create sAPPp and C99, which is further processed by Y-secretase.
• Y-Secretase: This complex, composed of presenilin-1 (PSEN1) or presenilin-2 (PSEN2), nicastrin, anterior pharynx-defective phenotype, and presenilin enhancer 2, cleaves C83 or C99, yielding either p3 or Ap and a fragment known as the APP intracellular domain (AICD).
Presenilins play a crucial role in the Y-secretase complex, impacting the cleavage of APP and thereby influencing Ap production. Mutations in presenilin genes are linked to familial Alzheimer's disease, leading to increased production of the toxic Ap42 isoform.
Implications of Secretases:
• BACE1 initiates Ap production, which can lead to plaque formation associated with AD.
• Y-Secretase is involved in various signaling pathways by cleaving over 80 substrates, including Notch (transmembrane receptor involved in cell development, differentiation, and neuronal functions), indicating a broad role in cellular function.
Despite its pathological role in Ap production, cleavage by secretases is essential for normal cellular functions and signaling pathways.
Globally, an increase in the number of patients with cognitive impairments has been observed, and this trend is expected to continue. As the population ages, the prevalence of dementia among the elderly has risen significantly [2], exerting a considerable impact not only on their families [2], [3] but also on the country's economy [4], [5]. [6], [7]. Given the projected increase in the elderly population, this issue is anticipated to escalate further. Therefore, the comprehension of dementia's pathogenesis and the formulation of preventive and therapeutic strategies are of paramount importance for the healthcare system. [6], [7]. [8]. [9].
Mechanism of Alzheimer's Disease Development Related to Beta-Amyloid
Production and Processing of Ap
Amyloid Precursor Protein (APP) Processing: Ap is derived from the amyloid precursor protein (APP) through enzymatic cleavage. The amyloidogenic pathway, primarily involving the
enzymes P-secretase (BACE1) and y-secretase, leads to the formation of Ap peptides, particularly AP(1-42) and AP(1-40).
Ap Peptide Variants: AP(1-42) is more prone to aggregation than AP(1-40), and the ratio of these two peptides is crucial in understanding disease onset and progression.
Aggregation and Oligomerization
• Multimerization: AP peptides can undergo multimerization, forming soluble oligomers and larger aggregates. Oligomerization occurs in two phases:
o Initial Phase: Soluble oligomers form from AP(1 -42) and are highly toxic to neurons,
disrupting synaptic function and causing cellular stress.
o Fibril Formation: Over time, these oligomers may aggregate further into insoluble
fibrils, which are less toxic but contribute to amyloid plaque formation.
o
Pathological Impact of Oligomers and Fibrils
• Toxicity of Soluble Oligomers: Soluble AP oligomers trigger neurotoxic events, including:
o Disruption of synaptic function, leading to cognitive deficits.
o Induction of oxidative stress and inflammatory responses.
o Interference with intracellular signaling pathways and calcium homeostasis.
• Insoluble Fibrils: While fibrils are generally considered less toxic than oligomers, they can still contribute to neurodegeneration through:
o Recruitment of additional AP peptides, perpetuating aggregation.
o Serving as reservoirs for soluble oligomers, thereby maintaining their toxic potential.
Neuroinflammatory Responses
• The accumulation of AP in the brain elicits an inflammatory response involving microglia (the brain's immune cells). Activated microglia can exacerbate neuroinflammation, leading to further neuronal damage and synaptic loss.
Neurofibrillary Tangles and Tau Pathology
• The presence of AP aggregates is closely linked to the development of neurofibrillary tangles, which are composed of hyperphosphorylated tau protein. AP oligomers are thought to promote tau pathology, further contributing to neurodegeneration.
• Studies in transgenic mouse models suggest that AP pathology precedes and drives tau pathology, indicating a hierarchical relationship in the progression of AD.
6. Animal Models and Insights
• Various animal models, including genetically modified mice, aged canines, and nonhuman primates, have been utilized to study AP deposition and its consequences. While no single model perfectly mimics human AD, they provide valuable insights into the mechanisms of AP toxicity and pathology.
• Mouse models have demonstrated that AP42 is the primary driver of amyloid deposition and that soluble oligomers are toxic to neurons, providing evidence that early interventions targeting AP may be beneficial.
7. Clinical Implications and Biomarkers
• Understanding the different states of AP (monomers, oligomers, and fibrils) is crucial for developing effective biomarkers and therapeutic strategies for AD. Imaging agents such as PIB selectively bind to different forms of AP, offering insights into the pathology of the disease.
• The complexity of AP interactions suggests the need for refined approaches to targeting AP-related pathology in AD, including immunotherapy and small-molecule inhibitors.
Conclusion:
The development of Alzheimer's disease related to beta-amyloid involves the production, aggregation, and pathological impact of AP peptides, particularly in their oligomeric forms.
The interplay between AP toxicity, neuroinflammation, and tau pathology culminates in the neurodegenerative processes characteristic of AD.
Continued research into the mechanisms of Ap and the dynamics of its different forms will be
critical for advancing our understanding and treatment of this devastating disease.
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