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    Understanding the neuronal synapse and challenges associated with the mitochondrial dysfunction in mild cognitive impairment and Alzheimer's disease
    (Elsevier B.V., 2023-09-13T00:00:00) Verma, Harkomal; Gangwar, Prabhakar; Yadav, Anuradha; Yadav, Bharti; Rao, Rashmi; Kaur, Sharanjot; Kumar, Puneet; Dhiman, Monisha; Taglialatela, Giulio; Mantha, Anil Kumar
    Synaptic mitochondria are crucial for maintaining synaptic activity due to their high energy requirements, substantial calcium (Ca2+) fluctuation, and neurotransmitter release at the synapse. To provide a continuous energy supply, neurons use special mechanisms to transport and distribute healthy mitochondria to the synapse while eliminating the damaged mitochondria from the synapse. Along the neuron, mitochondrial membrane potential (?) gradient exists and is highest in the somal region. Lower ? in the synaptic region renders mitochondria more vulnerable to oxidative stress-mediated damage. Secondly, mitochondria become susceptible to the release of cytochrome c, and mitochondrial DNA (mtDNA) is not shielded from the reactive oxygen species (ROS) by the histone proteins (unlike nuclear DNA), leading to activation of caspases and pronounced oxidative DNA base damage, which ultimately causes synaptic loss. Both synaptic mitochondrial dysfunction and synaptic failure are crucial factors responsible for Alzheimer's disease (AD). Furthermore, amyloid beta (A?) and hyper-phosphorylated Tau, the two leading players of AD, exaggerate the disease-like pathological conditions by reducing the mitochondrial trafficking, blocking the bi-directional transport at the synapse, enhancing the mitochondrial fission via activating the mitochondrial fission proteins, enhancing the swelling of mitochondria by increasing the influx of water through mitochondrial permeability transition pore (mPTP) opening, as well as reduced ATP production by blocking the activity of complex I and complex IV. Mild cognitive impairment (MCI) is also associated with decline in cognitive ability caused by synaptic degradation. This review summarizes the challenges associated with the synaptic mitochondrial dysfunction linked to AD and MCI and the role of phytochemicals in restoring the synaptic activity and rendering neuroprotection in AD. � 2023 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
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    Redefining oxidative stress in Alzheimer's disease: Targeting platelet reactive oxygen species for novel therapeutic options
    (Elsevier Inc., 2022-08-01T00:00:00) Beura, Samir Kumar; Dhapola, Rishika; Panigrahi, Abhishek Ramachandra; Yadav, Pooja; Reddy, Dibbanti Harikrishna; Singh, Sunil Kumar
    Alzheimer's disease (AD), a progressive neurodegenerative disorder, is considered one of the most common causes of dementia worldwide, accounting for about 80 % of all dementia cases. AD is manifested by the extraneuronal deposition of senile plaques of amyloid beta (A?) and intraneuronal accumulation of neurofibrillary tangles of phosphorylated tau. The impaired proteostasis of these filamentous A? and tau is significantly regulated by reactive oxygen species (ROS). ROS-induced oxidative stress (OS) is the cardinal cause behind neuroinflammation-triggered neurodegeneration during AD. Besides ROS-induced neuro-inflammation, AD is also associated with cerebrovascular dysfunction, where platelet primarily plays a significant role in blood-vessel integrity and tissue repair. Though platelets are the circulatory cell fragments that play predominant roles in thrombosis and hemostasis, their contributions to other physiological functions are also being elucidated. Surprisingly, platelets contribute about 90 % of the circulatory A? and share striking similarities with neurons in several aspects, including different neurotransmitters and their cognate receptors, thus considering platelets as potential peripheral models for AD. Interestingly, platelet structural and functional dysfunctions are evident in AD, where ROS production is associated with platelet hyperactivity. Although activated platelet carries several vital enzymes and immunomodulatory molecules, which can potentially exacerbate OS-mediated neuronal damage, and neurodegeneration, their mechanism of action and mode of progression, are still obscure. Therefore, in this review, we have described the detailed role of OS and platelet in AD, addressing the therapeutic approach and molecular mechanism of platelet-mediated ROS generation as a contributing factor in aggravating the disease. � 2022 Elsevier Inc.
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    Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease
    (Elsevier B.V., 2023-06-29T00:00:00) Bhatti, Jasvinder Singh; Kaur, Satinder; Mishra, Jayapriya; Dibbanti, Harikrishnareddy; Singh, Arti; Reddy, Arubala P.; Bhatti, Gurjit Kaur; Reddy, P. Hemachandra
    Alzheimer's disease (AD) is a neurodegenerative disease that manifests its pathology through synaptic damage, mitochondrial abnormalities, microRNA deregulation, hormonal imbalance, increased astrocytes & microglia, accumulation of amyloid ? (A?) and phosphorylated Tau in the brains of AD patients. Despite extensive research, the effective treatment of AD is still unknown. Tau hyperphosphorylation and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline in patients with AD. Mitochondrial dysfunction is evidenced by enhanced mitochondrial fragmentation, impaired mitochondrial dynamics, mitochondrial biogenesis and defective mitophagy in AD. Hence, targeting mitochondrial proteins might be a promising therapeutic strategy in treating AD. Recently, dynamin-related protein 1 (Drp1), a mitochondrial fission protein, has gained attention due to its interactions with A? and hyperphosphorylated Tau, altering mitochondrial morphology, dynamics, and bioenergetics. These interactions affect ATP production in mitochondria. A reduction in Drp1 GTPase activity protects against neurodegeneration in AD models. This article provides a comprehensive overview of Drp1's involvement in oxidative damage, apoptosis, mitophagy, and axonal transport of mitochondria. We also highlighted the interaction of Drp1 with A? and Tau, which may contribute to AD progression. In conclusion, targeting Drp1 could be a potential therapeutic approach for preventing AD pathology. � 2023