scholarly journals Mitochondrial Dysfunction as a Key Event during Aging: From Synaptic Failure to Memory Loss

2020 ◽  
Author(s):  
Claudia Jara ◽  
Angie K. Torres ◽  
Margrethe A. Olesen ◽  
Cheril Tapia-Rojas
Keyword(s):  
Mitochondrial Dysfunction ◽  
Memory Loss ◽  
Synaptic Failure

scholarly journals Pathologically phosphorylated tau at S396/404 (PHF-1) is accumulated inside of hippocampal synaptic mitochondria of aged Wild-type mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Angie K. Torres ◽  
Claudia Jara ◽  
Margrethe A. Olesen ◽  
Cheril Tapia-Rojas
Keyword(s):  
Mitochondrial Dysfunction ◽  
Brain Aging ◽  
Memory Loss ◽  
Proteinase K ◽  
Immunogold Electron Microscopy ◽  
Phosphorylated Tau ◽  
Aged Mice ◽  
Age Related ◽  
Synaptic Failure ◽  
Synaptic Mitochondria

AbstractBrain aging is a natural process characterized by cognitive decline and memory loss. This impairment is related to mitochondrial dysfunction and has recently been linked to the accumulation of abnormal proteins in the hippocampus. Age-related mitochondrial dysfunction could be induced by modified forms of tau. Here, we demonstrated that phosphorylated tau at Ser 396/404 sites, epitope known as PHF-1, is increased in the hippocampus of aged mice at the same time that oxidative damage and mitochondrial dysfunction are observed. Most importantly, we showed that tau PHF-1 is located in hippocampal mitochondria and accumulates in the mitochondria of old mice. Finally, since two mitochondrial populations were found in neurons, we evaluated tau PHF-1 levels in both non-synaptic and synaptic mitochondria. Interestingly, our results revealed that tau PHF-1 accumulates primarily in synaptic mitochondria during aging, and immunogold electron microscopy and Proteinase K protection assays demonstrated that tau PHF-1 is located inside mitochondria. These results demonstrated the presence of phosphorylated tau at PHF-1 commonly related to tauopathy, inside the mitochondria from the hippocampus of healthy aged mice for the first time. Thus, this study strongly suggests that synaptic mitochondria could be damaged by tau PHF-1 accumulation inside this organelle, which in turn could result in synaptic mitochondrial dysfunction, contributing to synaptic failure and memory loss at an advanced age.

scholarly journals Premature synaptic mitochondrial dysfunction in the hippocampus during aging contributes to memory loss

Redox Biology ◽  
2020 ◽  
Vol 34 ◽  
pp. 101558
Author(s):  
Margrethe A. Olesen ◽  
Angie K. Torres ◽  
Claudia Jara ◽  
Michael P. Murphy ◽  
Cheril Tapia-Rojas
Keyword(s):  
Mitochondrial Dysfunction ◽  
Memory Loss

scholarly journals FTY720 Prevents Spatial Memory Impairment in a Rat Model of Chronic Cerebral Hypoperfusion via a SIRT3-Independent Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Miao Zhang ◽  
Yuan Hu ◽  
Jiahui Zhang ◽  
Junjian Zhang
Keyword(s):  
Spatial Memory ◽  
Mitochondrial Dysfunction ◽  
Memory Performance ◽  
Memory Loss ◽  
Underlying Mechanism ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Sirtuin 3 ◽  
Vessel Occlusion ◽  
Cerebral Ischemic

Vascular dementia (VD) and Alzheimer's disease (AD) are the most prevalent types of late-life dementia. Chronic cerebral hypoperfusion (CCH) contributes to both AD and VD. Recently, accumulating evidence has indicated that fingolimod (FTY720) is neuroprotective in acute cerebral ischemic stroke animal models, and the drug is now being used in clinical translation studies. However, fewer studies have addressed the role of FTY720 in chronic cerebral hypoperfusion (CCH)-related brain damage. In the present study, to investigate whether FTY720 can improve CCH-induced spatial memory loss and its underlying mechanism, two-vessel occlusion (2VO) rats were administered intraperitoneal FTY720 (1 mg/kg) for 7 consecutive weeks from post-operative day 8. Spatial memory was tested using the Morris Water Maze (MWM), and the rats' brains were harvested to allow molecular, biochemical, and pathological tests. We found that FTY720 treatment significantly reduced the escape latency and increased the target quadrant swimming time of the 2VO rats in the MWM task. The improvement in memory performance paralleled lower levels of pro-inflammatory cytokines and Iba-1 positive cells in the hippocampus of the 2VO rats, indicating that FTY720 had a beneficial effect in mitigating neuroinflammation. Furthermore, we found that FTY720 alleviated mitochondrial dysfunction in 2VO rats, as manifested by lower malondialdehyde levels, higher ATP content, and upregulation of ATP synthase activity in the hippocampus after treatment. FTY720 had no effect on the CCH-induced decrease in the activity of hippocampal Sirtuin-3, a master regulator of mitochondrial function and neuroinflammation. In summary, the results showed that FTY720 can improve CCH-induced spatial memory loss. The mechanism may involve Sirtuin-3-independent regulation of mitochondrial dysfunction and neuroinflammation in the hippocampus. The present study provides new clues to the pathological mechanism of CCH-induced cognitive impairment.

scholarly journals Deciphering the role of PGC-1α in neurological disorders: from mitochondrial dysfunction to synaptic failure

2022 ◽  
Vol 17 (2) ◽  
pp. 237
Author(s):  
Jorge Fuentealba ◽  
JessicaD Panes ◽  
Aline Wendt ◽  
Oscar Ramirez-Molina ◽  
PatricioA Castro
Keyword(s):  
Mitochondrial Dysfunction ◽  
Neurological Disorders ◽  
Synaptic Failure

scholarly journals ROLE OF MITOCHONDRIAL DISFUNCTION IN THE DEVELOPMENT OF ALZHEIMER’S DISEASE

2021 ◽  
Vol 67 (1) ◽  
pp. 57-66
Author(s):  
V.V. Ganzha ◽  
◽  
E.A. Lukyanetz ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Tau Protein ◽  
Mitochondrial Dynamics ◽  
Memory Loss ◽  
Disease Process ◽  
Hyperphosphorylated Tau Protein ◽  
Amyloid Aβ

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intensive research have shown that multicellular changes are involved in AD’s development and progression, including mitochondrial damage, synaptic dysfunction, formation and accumulation of beta-amyloid (Aβ), formation and accumulation of hyperphosphorylated tau protein, and loss of neurons in patients with this disease. Among them, mitochondrial dysfunction and synaptic damage are the primary manifestations in the disease process. Recent studies have also shown that defective mitophagy caused by Aβ and tau protein are the main indicators in AD’s pathogenesis. This review includes an overview of recent researches on the role of mitochondria in AD development. The review summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics, changes in mitochondrial DNA, and calcium dyshomeostasis in AD pathogenesis

scholarly journals Synaptic Plasticity In Alzheimer’s Disease

2001 ◽  
Vol 19 (4) ◽  
pp. 711-717
Author(s):  
Daniel A.C. Montoya
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Plasticity ◽  
Early Detection ◽  
Cortical Plasticity ◽  
Memory Loss ◽  
Long Term Potentiation ◽  
Early Stages ◽  
Term Potentiation ◽  
Synaptic Failure

It has been proposed that Alzheimer’s disease is a synaptic failure associated with subtle memory loss during the early stages of the disorder. If this is the case, it should prove useful to elucidate the mechanisms of synaptic plasticity during early stages of the condition. On the other hand, Long Term Potentiation, one of the best-known mechanisms of synaptic plasticity has been recently confirmed absent in Alzheimer’s disease patients. This link may lead to focus efforts in early detection of synaptic failure and development of preventive approaches aiming to improve synaptic plasticity. Here we review some new evidence in the study of cortical plasticity in humans that could be applied to the early detection of the disorder.

scholarly journals Amyloid Beta and Phosphorylated Tau-Induced Defective Autophagy and Mitophagy in Alzheimer’s Disease

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 488 ◽  
Author(s):  
P. Hemachandra Reddy ◽  
Darryll MA Oliver
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Amyloid Beta ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Memory Loss ◽  
Disease Process ◽  
Neuronal Loss ◽  
Cellular Debris

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intense research have revealed that multiple cellular changes are implicated in the development and progression of AD, including mitochondrial damage, synaptic dysfunction, amyloid beta (Aβ) formation and accumulation, hyperphosphorylated tau (P-Tau) formation and accumulation, deregulated microRNAs, synaptic damage, and neuronal loss in patients with AD. Among these, mitochondrial dysfunction and synaptic damage are early events in the disease process. Recent research also revealed that Aβ and P-Tau-induced defective autophagy and mitophagy are prominent events in AD pathogenesis. Age-dependent increased levels of Aβ and P-Tau reduced levels of several autophagy and mitophagy proteins. In addition, abnormal interactions between (1) Aβ and mitochondrial fission protein Drp1; (2) P-Tau and Drp1; and (3) Aβ and PINK1/parkin lead to an inability to clear damaged mitochondria and other cellular debris from neurons. These events occur selectively in affected AD neurons. The purpose of our article is to highlight recent developments of a Aβ and P-Tau-induced defective autophagy and mitophagy in AD. This article also summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics (increased fission and reduced fusion), defective mitochondrial biogenesis, reduced ATP, increased free radicals and lipid peroxidation, and decreased cytochrome c oxidase (COX) activity and calcium dyshomeostasis in AD pathogenesis. Our article also discusses how reduced levels of Drp1, Aβ, and P-Tau can enhance the clearance of damaged mitochondria and other cellular debris by autophagy and mitophagy mechanisms.

scholarly journals Exercise-Induced Benefits for Alzheimer’s Disease by Stimulating Mitophagy and Improving Mitochondrial Function

2021 ◽  
Vol 13 ◽  
Author(s):  
Jiling Liang ◽  
Cenyi Wang ◽  
Hu Zhang ◽  
Jielun Huang ◽  
Juying Xie ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Mitochondrial Function ◽  
Early Stage ◽  
Memory Loss ◽  
Later Life ◽  
Cognitive Capacity ◽  
Neurodegenerative Process

Neurons are highly specialized post-mitotic cells that are inherently dependent on mitochondria due to their higher bioenergetic demand. Mitochondrial dysfunction is closely associated with a variety of aging-related neurological disorders, such as Alzheimer’s disease (AD), and the accumulation of dysfunctional and superfluous mitochondria has been reported as an early stage that significantly facilitates the progression of AD. Mitochondrial damage causes bioenergetic deficiency, intracellular calcium imbalance and oxidative stress, thereby aggravating β-amyloid (Aβ) accumulation and Tau hyperphosphorylation, and further leading to cognitive decline and memory loss. Although there is an intricate parallel relationship between mitochondrial dysfunction and AD, their triggering factors, such as Aβ aggregation and hyperphosphorylated Tau protein and action time, are still unclear. Moreover, many studies have confirmed abnormal mitochondrial biosynthesis, dynamics and functions will present once the mitochondrial quality control is impaired, thus leading to aggravated AD pathological changes. Accumulating evidence shows beneficial effects of appropriate exercise on improved mitophagy and mitochondrial function to promote mitochondrial plasticity, reduce oxidative stress, enhance cognitive capacity and reduce the risks of cognitive impairment and dementia in later life. Therefore, stimulating mitophagy and optimizing mitochondrial function through exercise may forestall the neurodegenerative process of AD.

scholarly journals Current Perspectives regarding Stem Cell-Based Therapy for Alzheimer’s Disease

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Kyeong-Ah Kwak ◽  
Seung-Pyo Lee ◽  
Jin-Young Yang ◽  
Young-Seok Park
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Stem Cell ◽  
Small Molecules ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Cell Based Therapy ◽  
Synaptic Failure ◽  
Excessive Accumulation

Alzheimer’s disease (AD), a progressive neurodegenerative disorder featuring memory loss and cognitive impairment, is caused by synaptic failure and the excessive accumulation of misfolded proteins. Many unsuccessful attempts have been made to develop new small molecules or antibodies to intervene in the disease’s pathogenesis. Stem cell-based therapies cast a new hope for AD treatment as a replacement or regeneration strategy. The results from recent preclinical studies regarding stem cell-based therapies are promising. Human clinical trials are now underway. However, a number of questions remain to be answered prior to safe and effective clinical translation. This review explores the pathophysiology of AD and summarizes the relevant stem cell research according to cell type. We also briefly summarize related clinical trials. Finally, future perspectives are discussed with regard to their clinical applications.

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