The Contribution of Long Non Coding RNAs (lncRNAs) to Alzheimer’s Disease: Mechanisms and Therapeutic Potential
The Contribution of Long Non Coding RNAs (lncRNAs) to Alzheimer’s Disease: Mechanisms and Therapeutic Potential
Golnaz Khodadadian,1,*Shokoofeh Salkhordeh,2
1. Department of Biology, Alzahra University, Tehran, Iran 2. Department of Biology, Islamic Azad University Central Tehran Branch, Tehran, Iran
Introduction: Alzheimer’s disease (AD) represents a significant challenge to public health, characterized as a chronic degenerative condition of the central nervous system (CNS) and recognized as the most prevalent form of dementia. This multifaceted disorder profoundly impacts cognitive functions, including memory, learning, comprehension, language, and judgment. The pathogenesis of AD is intricate, involving numerous interlinked signaling pathways and diverse cell types. A multitude of hypotheses regarding its etiology have been proposed; however, current consensus points to the accumulation of amyloid-beta plaques and tau tangles as pivotal factors in the disease’s progression. Despite ongoing research efforts, a definitive cure remains elusive, underscoring the urgent need for effective therapeutic interventions aimed at slowing disease progression or alleviating symptoms. This necessity highlights the importance of identifying reliable biomarkers that can enhance diagnostic accuracy, particularly in the disease's early stages. In this context, non-coding RNAs (ncRNAs) emerge as a promising area of investigation. Among these, long non-coding RNAs (lncRNAs) have been recognized for their significant roles in various pathological processes associated with AD, including amyloid production, tau hyperphosphorylation, and neuroinflammation.
Methods: Alzheimer’s disease (AD) poses a formidable challenge to public health, necessitating a deeper understanding of its complex pathogenesis. The accumulation of amyloid-beta plaques and tau tangles remains central to current models of AD progression; however, the multifactorial nature of the disease calls for a broader exploration of contributing factors. Our review underscores the emerging role of long non-coding RNAs (lncRNAs) in the regulatory networks that govern key pathological processes in AD, such as amyloid production, tau hyperphosphorylation, and neuroinflammation. The identification of specific lncRNAs associated with these processes not only enhances our understanding of AD's molecular underpinnings but also opens avenues for novel diagnostic and therapeutic strategies. As potential biomarkers, lncRNAs could facilitate earlier and more accurate diagnoses, which is critical for timely intervention.
Results: The investigation into the role of long non-coding RNAs (lncRNAs) in Alzheimer’s disease (AD) has revealed significant insights into their regulatory functions and potential as biomarkers and therapeutic targets. Our review highlights several key findings regarding the involvement of lncRNAs in critical pathological processes associated with AD.
Firstly, lncRNAs such as BACE1-AS and 51A have been identified as promoters of BACE1 expression, which is crucial for the cleavage of amyloid precursor protein (APP) and subsequent amyloid-beta (Aβ) accumulation. This accumulation is a hallmark of AD pathology, and the association of lncRNA 17A with alterations in the Aβ ratio further underscores the role of lncRNAs in neurodegeneration.
Secondly, the hyperphosphorylation of tau protein, which leads to neurofibrillary tangle formation, is significantly influenced by lncRNAs. Specifically, Linc00507 has been shown to facilitate tau hyperphosphorylation by promoting tau kinase activation, thereby contributing to the neurodegenerative processes, characteristic of AD.
Moreover, mitochondrial dysfunction, an early event in AD, is modulated by lncRNAs such as NEAT1. Dysregulation of NEAT1 has been linked to impaired autophagy and increased tau pathology, indicating a complex interplay between lncRNAs and mitochondrial health in the context of AD.
Synaptic impairment, a critical factor in cognitive decline, is also associated with lncRNAs. BC200 and BDNF-AS have been implicated in regulating synaptic dynamics, with disturbances in their expression correlating with cognitive deficits observed in AD patients.
Neuroinflammation, a significant contributor to AD pathology, is influenced by lncRNAs like MALAT1 and MEG3, which exhibit anti-inflammatory effects. This suggests that lncRNAs may hold therapeutic potential in modulating inflammatory responses in AD.
Lastly, the role of lncRNAs in neuronal apoptosis is highlighted by EBF3-AS and MALAT1, which modulate apoptotic signals and contribute to neuronal loss in AD.
Conclusion: In summary, our comprehensive review underscores the pivotal role of long non-coding RNAs in the pathogenesis of Alzheimer's disease. The evidence presented indicates that lncRNAs are intricately involved in key processes such as neuroinflammation, amyloid beta metabolism and tau pathology. Furthermore, their potential as biomarkers for early diagnosis and as therapeutic targets opens new avenues for intervention. Future research should focus on elucidating the precise mechanisms of lncRNA action and their clinical applicability in AD management, paving the way for innovative strategies in combating this devastating disease.