The Role of Mitochondrial Impairment in Alzheimer´s Disease Neurodegeneration: The Tau Connection

Quntanilla, Rodrigo A; Tapia-Monsalves, Carola

doi:10.2174/1570159x18666200525020259

Cited by 29 publications

(20 citation statements)

References 163 publications

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“…Two common pathologies associated with AD are changes to amyloid precursor protein (APP) procession leading to accumulation of amyloid beta peptide (Aβ) [ 20 ] or the hyperphosphorylation of tau protein [ 21 ]. In return, both of these pathological processes are also affecting mitochondrial bioenergetics [ 22 , 23 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

Esselun

Theyssen

Eckert

2021

IJMS

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(1) Background: Ellagitannins are natural products occurring in pomegranate and walnuts. They are hydrolyzed in the gut to release ellagic acid, which is further metabolized by the microflora into urolithins, such as urolithin A (UA). Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegenerative diseases. In this study, we investigated the neuroprotective activity of the metabolite UA against mitochondrial dysfunction in a cellular model of early Alzheimer disease (AD). (2) Methods: In the present study we used SH-SY5Y-APP695 cells and its corresponding controls (SH-SY5Ymock) to assess UA’s effect on mitochondrial function. Using these cells we investigated mitochondrial respiration (OXPHOS), mitochondrial membrane potential (MMP), adenosine triphosphate (ATP) production, autophagy and levels of reactive oxygen species (ROS) in cells treated with UA. Furthermore, we assessed UA’s effect on the expression of genes related to mitochondrial bioenergetics, mitochondrial biogenesis, and autophagy via quantitative real-time PCR (qRT-PCR). (3) Results: Treatment of SH-SY5Y-APP695 cells suggests changes to autophagy corresponding with qRT-PCR results. However, LC3B-I, LC3B-II, and p62 levels were unchanged. UA (10 µM) reduced MMP, and ATP-levels. Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS. Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695. Both cell lines showed unaltered levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which is commonly associated with mitochondrial biogenesis. Results imply that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes. (4) Conclusion: Urolithin A shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited. Instead, data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis.

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Section: Introductionmentioning

confidence: 99%

Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

Esselun

Theyssen

Eckert

2021

IJMS

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“…When mitochondria cannot be efficiently transported into synapses, ATP production and calcium buffering would be diminished, and the trafficking of glutamate receptor subunits to the postsynaptic membrane is impaired, ultimately resulting in synaptic dysfunction [ 113 ]. Pathological tau plays a vital role in impairing mitochondrial transport, thereby reducing the number of presynaptic mitochondria and hampering the release of synaptic vesicles [ 35 , 114 , 115 ]. In cultured neurons from P301L tau knock-in mice, the number of mitochondria is significantly decreased in axons and the volume of individual motile mitochondria increased, indicating that tau regulates mitochondrial functions [ 116 ].…”

Section: Pathological Tau and Mitochondrial Dysfunction At Synapsesmentioning

confidence: 99%

The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases

Zhang

Yin

et al. 2021

Transl Neurodegener

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Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, accompanied by amyloid-β (Aβ) overload and hyperphosphorylated tau accumulation in the brain. Synaptic dysfunction, an important pathological hallmark in AD, is recognized as the main cause of the cognitive impairments. Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD. Pathological tau, which is detached from axonal microtubules and mislocalized into pre- and postsynaptic neuronal compartments, is suggested to induce synaptic dysfunction in several ways, including reducing mobility and release of presynaptic vesicles, decreasing glutamatergic receptors, impairing the maturation of dendritic spines at postsynaptic terminals, disrupting mitochondrial transport and function in synapses, and promoting the phagocytosis of synapses by microglia. Here, we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD. We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.

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“…(mPTP), destroy the permeation barrier of IMM, and lead to the decrease of intermembrane potential (Szeto, 2014;Quntanilla and Tapia-Monsalves, 2020). At the same time, cyt C and other pro-apoptotic proteins escape into the cytoplasm through mPTP and trigger cell apoptosis and death (Szeto, 2014).…”

Section: Mitochondria Dysfunction Is Crucial For the Pathogenesis Of Neurodegenerative Diseasesmentioning

confidence: 99%

Role of Mitochondria in Neurodegenerative Diseases: From an Epigenetic Perspective

Zhang

Liu

et al. 2021

Front. Cell Dev. Biol.

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Mitochondria, the centers of energy metabolism, have been shown to participate in epigenetic regulation of neurodegenerative diseases. Epigenetic modification of nuclear genes encoding mitochondrial proteins has an impact on mitochondria homeostasis, including mitochondrial biogenesis, and quality, which plays role in the pathogenesis of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. On the other hand, intermediate metabolites regulated by mitochondria such as acetyl-CoA and NAD+, in turn, may regulate nuclear epigenome as the substrate for acetylation and a cofactor of deacetylation, respectively. Thus, mitochondria are involved in epigenetic regulation through bidirectional communication between mitochondria and nuclear, which may provide a new strategy for neurodegenerative diseases treatment. In addition, emerging evidence has suggested that the abnormal modification of mitochondria DNA contributes to disease development through mitochondria dysfunction. In this review, we provide an overview of how mitochondria are involved in epigenetic regulation and discuss the mechanisms of mitochondria in regulation of neurodegenerative diseases from epigenetic perspective.

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The Role of Mitochondrial Impairment in Alzheimer´s Disease Neurodegeneration: The Tau Connection

Cited by 29 publications

References 163 publications

Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease

The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases

Role of Mitochondria in Neurodegenerative Diseases: From an Epigenetic Perspective

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