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Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder which leads to mental deterioration due to aberrant accretion of misfolded proteins in the brain. According to mitochondrial cascade hypothesis, mitochondrial dysfunction is majorly involved in the pathogenesis of AD. Many drugs targeting mitochondria to treat and prevent AD are in different phases of clinical trials for the evaluation of safety and efficacy as mitochondria are involved in various cellular and neuronal functions. Mitochondrial dynamics is regulated by fission and fusion processes mediated by dynamin-related protein (Drp1). Inner membrane fusion takes place by OPA1 and outer membrane fusion is facilitated by mitofusin1 and mitofusin2 (Mfn1/2). Excessive calcium release also impairs mitochondrial functions; to overcome this, calcium channel blockers like nilvadipine are used. Another process acting as a regulator of mitochondrial function is mitophagy which is involved in the removal of damaged and non-functional mitochondria however this process is also altered in AD due to mutations in Presenilin1 (PS1) and Amyloid Precursor Protein (APP) gene. Mitochondrial dynamics is altered in AD which led to the discovery of various fission protein (like Drp1) inhibitors and drugs that promote fusion. Modulations in AMPK, SIRT1 and Akt pathways can also come out to be better therapeutic strategies as these pathways regulate functions of mitochondria. Oxidative phosphorylation is major generator of Reactive Oxygen Species (ROS) leading to mitochondrial damage; therefore reduction in production of ROS by using antioxidants like MitoQ, Curcumin and Vitamin Eis quiteeffective.

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  1. Department of Pharmacology, Central University of Punjab, 151401, Bathinda, India

    Rishika Dhapola & Dibbanti HariKrishna Reddy

  2. Department of Pharmacology, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Phulen Sarma, Bikash Medhi & Ajay Prakash

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  1. Rishika Dhapola
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Rishika Dhapola wrote the manuscript, Phulen Sarma wrote the manuscript, Bikash Medhi design and edited manuscript, Ajay Prakash edited manuscript, and Dibbanti HariKrishna Reddy designed, wrote, and edited manuscript.

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Correspondence to Dibbanti HariKrishna Reddy.

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Dhapola, R., Sarma, P., Medhi, B. et al. Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer’s Disease. Mol Neurobiol 59, 535–555 (2022). https://doi.org/10.1007/s12035-021-02612-6

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  • DOI: https://doi.org/10.1007/s12035-021-02612-6

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