scholarly journals Altered mitochondrial dynamics and function in APOE4-expressing astrocytes

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Eran Schmukler ◽  
Shira Solomon ◽  
Shira Simonovitch ◽  
Yona Goldshmit ◽  
Eya Wolfson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Transgenic Mice ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Major Risk Factor ◽  
Sporadic Alzheimer’S Disease ◽  
Dynamics And Function ◽  
And Function

Abstract APOE4 is a major risk factor for sporadic Alzheimer’s disease; however, it is unclear how it exerts its pathological effects. Others and we have previously shown that autophagy is impaired in APOE4 compared to APOE3 astrocytes, and demonstrated differences in the expression of mitochondrial dynamics proteins in brains of APOE3 and APOE4 transgenic mice. Here, we investigated the effect of APOE4 expression on several aspects of mitochondrial function and network dynamics, including fusion, fission, and mitophagy, specifically in astrocytes. We found that APOE3 and APOE4 astrocytes differ in their mitochondrial dynamics, suggesting that the mitochondria of APOE4 astrocytes exhibit reduced fission and mitophagy. APOE4 astrocytes also show impaired mitochondrial function. Importantly, the autophagy inducer rapamycin enhanced mitophagy and improved mitochondrial functioning in APOE4 astrocytes. Collectively, the results demonstrate that APOE4 expression is associated with altered mitochondrial dynamics, which might lead to impaired mitochondrial function in astrocytes. This, in turn, may contribute to the pathological effects of APOE4 in Alzheimer’s disease.

scholarly journals Mitochondrial links between brain aging and Alzheimer’s disease

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Heather M. Wilkins ◽  
Russell H. Swerdlow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Mitochondrial Function ◽  
Brain Aging ◽  
Major Risk Factor ◽  
Background Information ◽  
Modeling Studies

AbstractAdvancing age is a major risk factor for Alzheimer’s disease (AD). This raises the question of whether AD biology mechanistically diverges from aging biology or alternatively represents exaggerated aging. Correlative and modeling studies can inform this question, but without a firm grasp of what drives aging and AD it is difficult to definitively resolve this quandary. This review speculates over the relevance of a particular hallmark of aging, mitochondrial function, to AD, and further provides background information that is pertinent to and provides perspective on this speculation.

scholarly journals Circle of Willis Atherosclerosis Is a Risk Factor for Sporadic Alzheimer’s Disease

2003 ◽  
Vol 23 (11) ◽  
pp. 2055-2062 ◽  
Author(s):  
Alex E. Roher ◽  
Chera Esh ◽  
Tyler A. Kokjohn ◽  
Walter Kalback ◽  
Dean C. Luehrs ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Circle Of Willis ◽  
Sporadic Alzheimer’S Disease

scholarly journals Protective effects of a natural product, curcumin, against amyloid β induced mitochondrial and synaptic toxicities in Alzheimer's disease

2016 ◽  
Vol 64 (8) ◽  
pp. 1220-1234 ◽  
Author(s):  
P Hemachandra Reddy ◽  
Maria Manczak ◽  
Xiangling Yin ◽  
Mary Catharine Grady ◽  
Andrew Mitchell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Viability ◽  
Natural Product ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Amyloid Β ◽  
Synaptic Activity ◽  
Protective Effects

The purpose of our study was to investigate the protective effects of a natural product—‘curcumin’— in Alzheimer's disease (AD)-like neurons. Although much research has been done in AD, very little has been reported on the effects of curcumin on mitochondrial biogenesis, dynamics, function and synaptic activities. Therefore, the present study investigated the protective effects against amyloid β (Aβ) induced mitochondrial and synaptic toxicities. Using human neuroblastoma (SHSY5Y) cells, curcumin and Aβ, we studied the protective effects of curcumin against Aβ. Further, we also studied preventive (curcumin+Aβ) and intervention (Aβ+curcumin) effects of curcumin against Aβ in SHSY5Y cells. Using real time RT-PCR, immunoblotting and immunofluorescence analysis, we measured mRNA and protein levels of mitochondrial dynamics, mitochondrial biogenesis and synaptic genes. We also assessed mitochondrial function by measuring hydrogen peroxide, lipid peroxidation, cytochrome oxidase activity and mitochondrial ATP. Cell viability was studied using the MTT assay. Aβ was found to impair mitochondrial dynamics, reduce mitochondrial biogenesis and decrease synaptic activity and mitochondrial function. In contrast, curcumin enhanced mitochondrial fusion activity and reduced fission machinery, and increased biogenesis and synaptic proteins. Mitochondrial function and cell viability were elevated in curcumin treated cells. Interestingly, curcumin pre- and post-treated cells incubated with Aβ showed reduced mitochondrial dysfunction, and maintained cell viability and mitochondrial dynamics, mitochondrial biogenesis and synaptic activity. Further, the protective effects of curcumin were stronger in pretreated SHSY5Y cells than in post-treated cells, indicating that curcumin works better in prevention than treatment in AD-like neurons. Our findings suggest that curcumin is a promising drug molecule to treat AD patients.

scholarly journals Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Afzal Misrani ◽  
Sidra Tabassum ◽  
Li Yang
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Morphology ◽  
Therapeutic Approaches ◽  
The Impact ◽  
And Oxidative Stress

Mitochondria play a pivotal role in bioenergetics and respiratory functions, which are essential for the numerous biochemical processes underpinning cell viability. Mitochondrial morphology changes rapidly in response to external insults and changes in metabolic status via fission and fusion processes (so-called mitochondrial dynamics) that maintain mitochondrial quality and homeostasis. Damaged mitochondria are removed by a process known as mitophagy, which involves their degradation by a specific autophagosomal pathway. Over the last few years, remarkable efforts have been made to investigate the impact on the pathogenesis of Alzheimer’s disease (AD) of various forms of mitochondrial dysfunction, such as excessive reactive oxygen species (ROS) production, mitochondrial Ca2+ dyshomeostasis, loss of ATP, and defects in mitochondrial dynamics and transport, and mitophagy. Recent research suggests that restoration of mitochondrial function by physical exercise, an antioxidant diet, or therapeutic approaches can delay the onset and slow the progression of AD. In this review, we focus on recent progress that highlights the crucial role of alterations in mitochondrial function and oxidative stress in the pathogenesis of AD, emphasizing a framework of existing and potential therapeutic approaches.

scholarly journals Age-Associated Epigenetic Alterations, Somatic Mutations, and Their Crosstalk in Alzheimer’s Disease

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 636-637
Author(s):  
Yaroslav Markov ◽  
Kyra Thrush ◽  
Morgan Levine
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Somatic Mutations ◽  
Brain Regions ◽  
Major Risk Factor ◽  
Postmortem Brain ◽  
Biological Aging ◽  
Learning Approaches ◽  
Age Related

Abstract Aging is the major risk factor for Alzheimer’s Disease (AD), and as life expectancy increases, neurodegeneration will continue to afflict an ever-increasing proportion of the population. While numerous theories are attempting to explain the drivers behind AD pathology, what unites them is the observation that AD is reliably associated with a progressive buildup of age-related molecular changes. Because of the varying clinical presentations of AD in patients with similar genetic backgrounds, it has been postulated that epigenetics may be implicated in its etiology. Building on our prior work showing that AD pathology is linked to alterations in age-related DNA CpG methylation (DNAme) across various brain regions, we use state-of-the-art machine learning approaches to identify patterns of molecular damage in postmortem brain samples. We show that alterations in DNAme are associated with accelerated biological aging, AD, and the APOE e4 genotype, which is a major risk factor for AD. We also demonstrate that these associations are present in the PFC but not cerebellum -- in line with the current understanding of AD progression in the brain. Finally, we perform whole-exome sequencing and protein mass spectrometry on the same brain samples to test our hypothesis as to whether AD-associated alterations of DNAme are linked with the accumulation of somatic mutations that affect the structural and binding properties of protein epigenetic regulators.

scholarly journals The Molecular Basis for Apolipoprotein E4 as the Major Risk Factor for Late-Onset Alzheimer's Disease

2019 ◽  
Vol 431 (12) ◽  
pp. 2248-2265 ◽  
Author(s):  
Ana-Caroline Raulin ◽  
Lucas Kraft ◽  
Youssra K. Al-Hilaly ◽  
Wei-Feng Xue ◽  
John E. McGeehan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Molecular Basis ◽  
Late Onset ◽  
Major Risk Factor ◽  
Apolipoprotein E4

scholarly journals A High Fat/Cholesterol Diet Recapitulates Some Alzheimer’s Disease-Like Features in Mice: Focus on Hippocampal Mitochondrial Dysfunction

2021 ◽  
pp. 1-15
Author(s):  
Gianni Mancini ◽  
Candida Dias ◽  
Catia F. Lourenço ◽  
Joao Laranjinha ◽  
Andreza de Bem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Risk Factor ◽  
Mitochondrial Dysfunction ◽  
Cognitive Performance ◽  
Mitochondrial Function ◽  
No Production ◽  
Cholesterol Diet ◽  
High Fat ◽  
Ample Evidence

Background: Ample evidence from clinical and pre-clinical studies suggests mid-life hypercholesterolemia as a risk factor for developing Alzheimer’s disease (AD) at a later age. Hypercholesterolemia induced by dietary habits can lead to vascular perturbations that increase the risk of developing sporadic AD. Objective: To investigate the effects of a high fat/cholesterol diet (HFCD) as a risk factor for AD by using a rodent model of AD and its correspondent control (healthy animals). Methods: We compared the effect of a HFCD in normal mice (non-transgenic mice, NTg) and the triple transgenic mouse model of AD (3xTgAD). We evaluated cognitive performance in relation to changes in oxidative metabolism and neuron-derived nitric oxide (•NO) concentration dynamics in hippocampal slices as well as histochemical staining of markers of the neurovascular unit. Results: In NTg, the HFCD produced only moderate hypercholesterolemia but significant decline in spatial memory was observed. A tendency for decrease in •NO production was accompanied by compromised mitochondrial function with decrease in spare respiratory capacity. In 3xTgAD mice, a robust increase in plasma cholesterol levels with the HFCD did not worsen cognitive performance but did induce compromise of mitochondrial function and significantly decreased •NO production. We found increased staining of biomarkers for astrocyte endfeet and endothelial cells in 3xTgAD hippocampi, which was further increased by the HFCD. Conclusion: A short term (8 weeks) intervention with HFCD can produce an AD-like phenotype even in the absence of overt systemic hypercholesterolemia and highlight mitochondrial dysfunction as a link between hypercholesterolemia and sporadic AD.

A genetic variation of cathepsin D is a major risk factor for Alzheimer's disease

2000 ◽  
Vol 47 (3) ◽  
pp. 399-403 ◽  
Author(s):  
Andreas Papassotiropoulos ◽  
Metin Bagli ◽  
Alexander Kurz ◽  
Johannes Kornhuber ◽  
Hans F�rstl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variation ◽  
Risk Factor ◽  
Cathepsin D ◽  
Major Risk Factor
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