Journal of Dementia
Open Access

Alzheimer's disease; Parkinson's disease; Neurodegeneration; Amyloid-beta; tau; Alpha-synuclein; Neuroinflammation.

Introduction

Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are chronic and debilitating disorders that progressively impair cognitive and motor functions, respectively. Both diseases primarily affect the central nervous system and lead to irreversible neuronal damage, although they differ significantly in their clinical presentation, neuropathology, and molecular mechanisms. AD is the leading cause of dementia, characterized by memory loss, confusion, and impaired cognitive function. PD, on the other hand, is the second most common neurodegenerative disorder, affecting movement control and leading to tremors, rigidity, and bradykinesia. The pathophysiology of AD involves the accumulation of amyloid-beta (Aβ) plaques and tau protein tangles, which disrupt neuronal communication and trigger neuroinflammation. Aβ plaques accumulate in the extracellular space, while tau tangles form inside neurons, resulting in synaptic dysfunction and neuronal loss. These features are often accompanied by microglial activation, contributing to neuroinflammation, which further exacerbates the disease. In contrast, PD is primarily characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to reduced dopamine levels in the brain. This depletion of dopamine is associated with the formation of Lewy bodies, intracellular inclusions composed mainly of alpha-synuclein, which are considered a hallmark of PD pathology [1-4].

Despite their differences, there are several overlapping features between AD and PD. Both diseases exhibit protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, and neuroinflammation as common underlying mechanisms. Moreover, both conditions present a progressive and irreversible course, often resulting in significant disability and a diminished quality of life for affected individuals. Understanding the molecular pathways that contribute to these diseases is crucial for identifying potential therapeutic targets and developing effective treatments to alleviate symptoms and slow disease progression. This study aims to compare and contrast the molecular mechanisms of neurodegeneration in AD and PD, focusing on protein aggregation, neuroinflammation, oxidative stress, and mitochondrial dysfunction, in order to highlight shared and unique aspects of their pathogenesis [5].

Methods

To investigate the mechanisms of neurodegeneration in Alzheimer's disease (AD) and Parkinson's disease (PD), a comprehensive review of the current literature was conducted. This review focused on peer-reviewed articles, clinical studies, and experimental research that explore the molecular and cellular pathways implicated in AD and PD pathogenesis. The primary sources of information included studies on protein misfolding and aggregation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. In the case of AD, the literature was examined to assess the roles of amyloid-beta (Aβ) plaques and tau tangles, with an emphasis on their effects on neuronal function and synaptic integrity. In addition, studies on the activation of microglia and astrocytes, as well as inflammatory cytokines, were analyzed to determine the contribution of neuroinflammation to disease progression. For PD, the review focused on the role of alpha-synuclein aggregation and the formation of Lewy bodies. Research related to the loss of dopaminergic neurons in the substantia nigra was also explored, as well as the involvement of mitochondrial dysfunction and oxidative stress. Furthermore, studies examining genetic mutations, such as those in the LRRK2 and PARK7 genes, were reviewed to understand their impact on neurodegeneration. Comparative analysis of both diseases was performed to identify common pathways, including protein aggregation, mitochondrial dysfunction, and neuroinflammation. The review also highlighted potential therapeutic targets that may address the shared mechanisms of neurodegeneration in AD and PD, with a particular focus on molecular interventions aimed at halting disease progression [6-8].

Results

The review revealed several shared and distinct mechanisms of neurodegeneration between Alzheimer's disease (AD) and Parkinson's disease (PD). In AD, the accumulation of amyloid-beta (Aβ) plaques and tau protein tangles were identified as key contributors to neuronal damage and synaptic dysfunction. Aβ plaques promote synaptic loss and disrupt neuronal communication, while tau tangles cause intracellular damage, impairing axonal transport and leading to neurodegeneration. Both features are accompanied by neuroinflammation, where activated microglia and astrocytes release pro-inflammatory cytokines that exacerbate neuronal damage. For PD, the aggregation of alpha-synuclein into Lewy bodies was found to be central to the pathology, leading to the progressive loss of dopaminergic neurons in the substantia nigra. The depletion of dopamine causes motor dysfunction, which is the hallmark of PD. Moreover, mitochondrial dysfunction, oxidative stress, and impaired autophagy were identified as key mechanisms in PD, contributing to neuronal death and the progression of the disease. Similar to AD, neuroinflammation also plays a role in PD, with microglial activation observed in affected brain regions. A significant overlap between AD and PD is the involvement of mitochondrial dysfunction and oxidative stress, which contribute to neuronal vulnerability in both conditions. In addition, protein aggregation and neuroinflammation were identified as common factors, suggesting that targeting these pathways could be beneficial for treating both diseases. Genetic mutations, particularly in genes such as LRRK2 in PD and APP in AD, were also highlighted as significant contributors to the diseases' development.

Discussion

The molecular mechanisms of neurodegeneration in Alzheimer's disease (AD) and Parkinson's disease (PD) exhibit both shared and unique features, which provide insights into potential therapeutic approaches. One of the major commonalities between the two diseases is the role of protein misfolding and aggregation. In AD, amyloid-beta plaques and tau tangles disrupt neuronal function and initiate a cascade of events that culminate in cell death. Similarly, in PD, alpha-synuclein aggregates into Lewy bodies, causing dopaminergic neuron degeneration. These protein aggregates not only directly impair neuronal function but also activate neuroinflammatory pathways that contribute to the neurodegenerative process. Neuroinflammation is a critical feature in both diseases, with activated microglia and astrocytes producing inflammatory cytokines that exacerbate neuronal damage. Chronic neuroinflammation can lead to a vicious cycle of cell death, making it a target for potential therapeutic intervention. Mitochondrial dysfunction and oxidative stress are other shared mechanisms, both contributing to neuronal vulnerability in AD and PD. Mitochondria play a central role in maintaining cellular energy homeostasis, and their dysfunction leads to increased oxidative damage, which further accelerates neurodegeneration. Despite these commonalities, the pathophysiology of AD and PD diverges in certain areas. In AD, the neurodegenerative process primarily affects cortical regions involved in memory and cognition, whereas in PD, the degeneration of dopaminergic neurons in the substantia nigra primarily leads to motor impairments. The distinct clinical manifestations and brain regions affected suggest that different therapeutic strategies may be required to target the unique aspects of each disease while considering their shared underlying mechanisms.

Conclusion

This comparative study of Alzheimer's disease (AD) and Parkinson's disease (PD) highlights both the similarities and differences in their molecular mechanisms of neurodegeneration. Both diseases are characterized by protein aggregation, neuroinflammation, mitochondrial dysfunction, and oxidative stress, which contribute to neuronal damage and disease progression. In AD, amyloid-beta plaques and tau tangles play a central role, while in PD, alpha-synuclein aggregation leads to the formation of Lewy bodies and dopaminergic neuron loss. Despite these similarities, the diseases affect different brain regions, with AD primarily impacting cortical areas associated with memory and cognition, while PD targets motor pathways through the degeneration of dopaminergic neurons. The shared mechanisms between AD and PD suggest potential therapeutic targets, including interventions aimed at reducing protein aggregation, modulating neuroinflammation, and improving mitochondrial function. However, given the distinct clinical presentations of these diseases, personalized approaches that address the unique aspects of each disorder are necessary. Further research into the molecular pathways underlying both diseases will be crucial in developing effective treatments to slow or halt neurodegeneration and improve the quality of life for affected individuals.

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