Mitochondrial Dysfunction: a Potential Therapeutic Target to Treat Alzheimer’s Disease

Nand, Sachchida; Singh, Charan; Singh, Arti; Singh, Mohan; Singh, Brijesh Kumar

doi:10.1007/s12035-020-01945-y

Cited by 108 publications

(57 citation statements)

References 139 publications

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“…Moreover, AD brains are characterized by mitochondrial fission and fusion dysregulation, shifting toward fission and resulting in abnormal free radicals’ production [ 60 , 61 ]. Tau accumulation also induces impairment of mitophagy [ 62 ], the physiological process that selectively degrades damaged mitochondria [ 63 ]. On the other hand, it has been shown that increased mitochondrial oxidative stress can induce tau hyper-phosphorylation.…”

Section: The Role Of Tau In Physiological Condition In Axonsmentioning

confidence: 99%

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

Vacchi

Kaelin‐Lang

Melli

2020

IJMS

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In neuronal cells, tau is a microtubule-associated protein placed in axons and alpha synuclein is enriched at presynaptic terminals. They display a propensity to form pathologic aggregates, which are considered the underlying cause of Alzheimer’s and Parkinson’s diseases. Their functional impairment induces loss of axonal transport, synaptic and mitochondrial disarray, leading to a “dying back” pattern of degeneration, which starts at the periphery of cells. In addition, pathologic spreading of alpha-synuclein from the peripheral nervous system to the brain through anatomical connectivity has been demonstrated for Parkinson’s disease. Thus, examination of the extent and types of tau and alpha-synuclein in peripheral tissues and their relation to brain neurodegenerative diseases is of relevance since it may provide insights into patterns of protein aggregation and neurodegeneration. Moreover, peripheral nervous tissues are easily accessible in-vivo and can play a relevant role in the early diagnosis of these conditions. Up-to-date investigations of tau species in peripheral tissues are scant and have mainly been restricted to rodents, whereas, more evidence is available on alpha synuclein in peripheral tissues. Here we aim to review the literature on the functional role of tau and alpha synuclein in physiological conditions and disease at the axonal level, their distribution in peripheral tissues, and discuss possible commonalities/diversities as well as their interaction in proteinopathies.

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Section: The Role Of Tau In Physiological Condition In Axonsmentioning

confidence: 99%

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

Vacchi

Kaelin‐Lang

Melli

2020

IJMS

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“…Although the mechanism is not clear, it is believed that the build-up of amyloid beta protein plaques seen in the brain plays an important role in Alzheimer’s disease. Numerous studies have shown that the amyloid beta peptide exerts neurotoxic effects possibly via mitochondrial dysfunction [ 20 , 79 , 80 , 81 ].…”

Section: Role Of Carnitine In Diseasementioning

confidence: 99%

The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation

Virmani¹,

Cirulli²

2022

IJMS

117

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Mitochondria control cellular fate by various mechanisms and are key drivers of cellular metabolism. Although the main function of mitochondria is energy production, they are also involved in cellular detoxification, cellular stabilization, as well as control of ketogenesis and glucogenesis. Conditions like neurodegenerative disease, insulin resistance, endocrine imbalances, liver and kidney disease are intimately linked to metabolic disorders or inflexibility and to mitochondrial dysfunction. Mitochondrial dysfunction due to a relative lack of micronutrients and substrates is implicated in the development of many chronic diseases. L-carnitine is one of the key nutrients for proper mitochondrial function and is notable for its role in fatty acid oxidation. L-carnitine also plays a major part in protecting cellular membranes, preventing fatty acid accumulation, modulating ketogenesis and glucogenesis and in the elimination of toxic metabolites. L-carnitine deficiency has been observed in many diseases including organic acidurias, inborn errors of metabolism, endocrine imbalances, liver and kidney disease. The protective effects of micronutrients targeting mitochondria hold considerable promise for the management of age and metabolic related diseases. Preventing nutrient deficiencies like L-carnitine can be beneficial in maintaining metabolic flexibility via the optimization of mitochondrial function. This paper reviews the critical role of L-carnitine in mitochondrial function, metabolic flexibility and in other pathophysiological cellular mechanisms.

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“…Alzheimer's disease (AD) is an irreversible neurodegenerative disease with cognitive impairment that accounts for more than half of patients with dementia (Knopman et al, 2021). To date, while the complexity of neurodegeneration continues to be explored and recognized, AD has been characterized in part by excessive extracellular beta-amyloid (Aβ) plaque accumulation, the presence of intracellular tau-containing neurofibrillary tangles, and neuroinflammation in the brain (Erika et al, 2018;Rai et al, 2020;Knopman et al, 2021;Singh et al, 2021). In the brains of patients with AD, synaptic loss can precede neurodegeneration, brain tissue gradually shrinks, which, in turn, leads to a decline in memory and learning abilities of patients, eventually causing dementia (Blennow et al, 2006;Srivastava et al, 2019;Tripathi et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Effects of α-Lipoic Acid on Phagocytosis of Oligomeric Beta-Amyloid1–42 in BV-2 Mouse Microglial Cells

Chang

et al. 2022

Front. Aging Neurosci.

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Background and objectives: This study aimed to investigate the enhancing effect of vitamin-like alpha-lipoic acid (ALA) on phagocytosis of oligomeric beta-amyloid (oAβ)1–42 in BV-2 mouse microglial cells.Methods: An in vitro model was established to investigate phagocytosis of oAβ1–42 in BV-2 cells. Transmission electron microscopy images indicated that the morphology of prepared oAβ1–42 was spherical particles. BV-2 cells treated with ALA were incubated with 5(6)-carboxyfluorescein-labeled oAβ1–42 (FAM-oAβ1–42) for 24 h, followed by flow cytometer analysis, western blotting, real-time quantitative PCR, and immunocytochemistry (ICC) analysis to assess the in vitro phagocytosis ability of oAβ1–42.Results: Alpha-lipoic acid significantly increased messenger RNA (mRNA) expression of the CD36 receptor in BV-2 cells. ICC analysis showed that ALA significantly elevated CD36 protein expression in BV-2 cells both with and without oAβ1–42 treatment. Results from the flow cytometry analysis indicated that the CD36 receptor inhibitor significantly attenuated ALA-promoted phagocytosis of FAM-oAβ1–42 in BV-2 cells. Moreover, ICC analysis revealed that ALA caused the translocation of peroxisome proliferator-activated receptor-γ (PPAR-γ), which is known to regulate the expression of CD36 mRNA in BV-2 cells. ALA also elevated both the mRNA and protein expression of cyclooxygenase-2 (COX-2), which is a key enzyme involved in the synthesis of 15-deoxy-Δ12,14-prostaglandin J2 in BV-2 cells.Conclusion: We postulated that ALA enhances oAβ1–42 phagocytosis by upregulating the COX-2/15-deoxy-Δ12,14-prostaglandin J2/PPAR-γ/CD36 pathway in BV-2 cells. Finally, future studies should be conducted with an in vivo study to confirm the findings.

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Mitochondrial Dysfunction: a Potential Therapeutic Target to Treat Alzheimer’s Disease

Cited by 108 publications

References 139 publications

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

Tau and Alpha Synuclein Synergistic Effect in Neurodegenerative Diseases: When the Periphery Is the Core

The Role of l-Carnitine in Mitochondria, Prevention of Metabolic Inflexibility and Disease Initiation

Effects of α-Lipoic Acid on Phagocytosis of Oligomeric Beta-Amyloid1–42 in BV-2 Mouse Microglial Cells

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