Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches

Xiong, Yan; Zhang, Yu; Luo, Jun; Zhu, Tongyu; Zhao, Ruihua; Mu, Benrong; Lu, Mei-Hong

doi:10.1007/s00210-023-02636-w

Cited by 5 publications

(1 citation statement)

References 252 publications

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“…In turn, the reduction of plasmin and tPA activities promotes Aβ accumulation by reducing Aβ clearance [ 56 ]. As well, Aβ-induced tPA dysfunction leads to neurovascular disorders [ 57 ]. Thus, exogenous tPA or pharmacological inhibition of PAI-1 can attenuate Aβ-induced neurovascular dysfunction [ 56 ].…”

Section: Plasminogen Activating System In Admentioning

confidence: 99%

The probable role of tissue plasminogen activator/neuroserpin axis in Alzheimer’s disease: a new perspective

Ali,

Al-kuraishy,

Al-Gareeb

et al. 2023

Acta Neurol Belg

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Alzheimer’s disease (AD) is the most common type of dementia associated with amyloid beta (Aβ) deposition. Dysfunction of the neuronal clearance pathway promotes the accumulation of Aβ. The plasminogen-activating system (PAS) is controlled by various enzymes like tissue plasminogen activators (tPA). Neuronal tPA enhances the conversion of plasminogen to plasmin, which cleaves Aβ; this function is controlled by many inhibitors of PAS, including a plasminogen-activating inhibitor (PAI-1) and neuroserpin. Therefore, the objective of the present narrative review was to explore the potential role of tPA/neuroserpin in the pathogenesis of AD. PAI-1 activity is increased in AD, which is involved in accumulating Aβ. Progressive increase of Aβ level during AD neuropathology is correlated with the over-production of PAI-1 with subsequent reduction of plasmin and tPA activities. Reducing plasmin and tPA activities promote Aβ by reducing Aβ clearance. Neuroserpin plays a critical role in the pathogenesis of AD as it regulates the expression and accumulation of Aβ. Higher expression of neuroserpin inhibits the neuroprotective tPA and the generation of plasmin with subsequent reduction in the clearance of Aβ. These observations raise conflicting evidence on whether neuroserpin is neuroprotective or involved in AD progression. Thus, neuroserpin over-expression with subsequent reduction of tPA may propagate AD neuropathology. Graphical abstract

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Section: Plasminogen Activating System In Admentioning

confidence: 99%

The probable role of tissue plasminogen activator/neuroserpin axis in Alzheimer’s disease: a new perspective

Ali,

Al-kuraishy,

Al-Gareeb

et al. 2023

Acta Neurol Belg

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The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration

Bradshaw,

Aldridge,

Jamerson

et al. 2024

Mol Neurobiol

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Causal links between mitophagy and Alzheimer’s disease: a Mendelian randomization study

Zhang,

Chen,

Guo

et al. 2024

Preprint

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Background Emerging evidence highlights the dysregulation of mitophagy, the process of clearing damaged mitochondria, as a potential contributor to Alzheimer's disease (AD) pathology. However, the precise mechanisms linking mitophagy to AD remain poorly understood. This study utilized summary-data-based Mendelian Randomization (SMR) combined with multi-omics data to explore the causal relationships between them, and to uncover potential epigenetic mechanisms of gene regulation. Methods Mitophagy-related genes were identified through the integration of three databases, and transcriptomic data of AD patients were obtained from the Gene Expression Omnibus (GEO) database. A meta-analysis was conducted to recognize differentially expressed genes (DEGs) associated with mitophagy in AD. Through SMR tools, genome-wide association study (GWAS) summary data of AD from the GWAS Catalog (n=487,511) were separately integrated with expression quantitative trait loci (eQTLs) and DNA methylation quantitative trait loci (mQTLs) from blood and brain tissues to identify potentially causal genes and methylation sites. The findings from primary analysis were validated with data from the UK Biobank (n=301,478). Results In total, 111 mitophagy-related genes were found to be differentially expressed in AD. The three-step SMR analysis identified two genes, PARL and BCL2L1, from blood tissues and three genes, ATG13, TOMM22, and SPATA33, from brain tissues as causal candidate genes associated with AD. The analysis pinpointed the possible epigenetic mechanisms, where specific methylation sites regulate the expression of these genes, potentially contributing to their association with AD. All findings were successfully replicated in UK Biobank cohorts. Conclusions The study emphasized the putatively causal relationships of mitophagy-related gene with AD. These underlying pathogenic mechanisms could pave the way for new approaches in early detection and therapeutic intervention for AD.

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Targeting mitophagy for neurological disorders treatment: advances in drugs and non-drug approaches

Cited by 5 publications

References 252 publications

The probable role of tissue plasminogen activator/neuroserpin axis in Alzheimer’s disease: a new perspective

The probable role of tissue plasminogen activator/neuroserpin axis in Alzheimer’s disease: a new perspective

The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration

Causal links between mitophagy and Alzheimer’s disease: a Mendelian randomization study

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