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

Jara, Claudia; Torres, Angie K.; Olesen, Margrethe A.; Tapia-Rojas, Cheril

doi:10.5772/intechopen.88445

Cited by 10 publications

(27 citation statements)

References 146 publications

(184 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The hippocampus is susceptible to aging ( Bartsch and Wulff, 2015 ). Neurobiological alterations in the aged hippocampus include oxidative damage and altered communication among neurons ( Bettio et al, 2017 ; Jara et al, 2019 ). These events result in impaired hippocampal function, affecting learning and memory ( Bettio et al, 2017 ; Jara et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

“…Neurobiological alterations in the aged hippocampus include oxidative damage and altered communication among neurons ( Bettio et al, 2017 ; Jara et al, 2019 ). These events result in impaired hippocampal function, affecting learning and memory ( Bettio et al, 2017 ; Jara et al, 2019 ). Pathological forms of tau have been linked to memory-related disorders, such as AD ( Amadoro et al, 2010 ; Pooler et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

“…Mitochondria are organelles required for ATP generation, calcium regulation, and maintenance of redox balance ( Sebastian et al, 2017 ; Perez et al, 2018a ). Mitochondrial dysfunction has been proposed as the common denominator connecting aging and the pathogenesis of AD ( Du et al, 2012 ; Jara et al, 2019 ; Wu et al, 2019 ). Indeed, mitochondrial and synaptic dysfunction are the early characteristics of AD ( Perez et al, 2018a ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Tau Deletion Prevents Cognitive Impairment and Mitochondrial Dysfunction Age Associated by a Mechanism Dependent on Cyclophilin-D

et al. 2021

Self Cite

View full text Add to dashboard Cite

Aging is an irreversible process and the primary risk factor for the development of neurodegenerative diseases, such as Alzheimer’s disease (AD). Mitochondrial impairment is a process that generates oxidative damage and ATP deficit; both factors are important in the memory decline showed during normal aging and AD. Tau is a microtubule-associated protein, with a strong influence on both the morphology and physiology of neurons. In AD, tau protein undergoes post-translational modifications, which could play a relevant role in the onset and progression of this disease. Also, these abnormal forms of tau could be present during the physiological aging that could be related to memory impairment present during this stage. We previously showed that tau ablation improves mitochondrial function and cognitive abilities in young wild-type mice. However, the possible contribution of tau during aging that could predispose to the development of AD is unclear. Here, we show that tau deletion prevents cognitive impairment and improves mitochondrial function during normal aging as indicated by a reduction in oxidative damage and increased ATP production. Notably, we observed a decrease in cyclophilin-D (CypD) levels in aged tau−/− mice, resulting in increased calcium buffering and reduced mitochondrial permeability transition pore (mPTP) opening. The mPTP is a mitochondrial structure, whose opening is dependent on CypD expression, and new evidence suggests that this could play an essential role in the neurodegenerative process showed during AD. In contrast, hippocampal CypD overexpression in aged tau−/− mice impairs mitochondrial function evidenced by an ATP deficit, increased mPTP opening, and memory loss; all effects were observed in the AD pathology. Our results indicate that the absence of tau prevents age-associated cognitive impairment by maintaining mitochondrial function and reducing mPTP opening through a CypD-dependent mechanism. These findings are novel and represent an important advance in the study of how tau contributes to the cognitive and mitochondrial failure present during aging and AD in the brain.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tau Deletion Prevents Cognitive Impairment and Mitochondrial Dysfunction Age Associated by a Mechanism Dependent on Cyclophilin-D

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, the cellular and molecular mechanisms leading to age-associated alterations are not completely clear 60 . Increasing evidence shows that synaptic dysfunction 61 and mitochondrial impairment 62 – 64 are considered early events during aging and in the pathogenesis of neurodegenerative disorders 63 . Also, mitochondrial dysfunction is considered a hallmark of aging 6 , 63 , because its functional deterioration contributes to the aged phenotype 63 , 65 .…”

Section: Discussionmentioning

confidence: 99%

“…Increasing evidence shows that synaptic dysfunction 61 and mitochondrial impairment 62 – 64 are considered early events during aging and in the pathogenesis of neurodegenerative disorders 63 . Also, mitochondrial dysfunction is considered a hallmark of aging 6 , 63 , because its functional deterioration contributes to the aged phenotype 63 , 65 . Considering the high-energy requirements of neurons to adequately perform all their functions in the brain, it is logical to hypothesize that an energy imbalance could lead to neurodegenerative pathologies.…”

Section: Discussionmentioning

confidence: 99%

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

Torres

Jara

Olesen

et al. 2021

Sci Rep

Self Cite

View full text Add to dashboard Cite

Brain 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.

show abstract

New findings about comparing the effects of antibiotic therapy and phage therapy on memory and hippocampal pyramidal cells in rats

Darbandi,

Komijani,

Tajiani

2023

Clinical Laboratory Analysis

View full text Add to dashboard Cite

BackgroundPseudomonas aeruginosa is a significant cause of infection in burn wounds. Antibiotics are widely used to treat infectious diseases, and alongside their therapeutic benefits, they can damage host cells. Significant side effects, such as nephrotoxicity and neurotoxicity, are observed in 60% of patients treated with colistin. Therefore, using a suitable alternative instead of antibiotics is paramount. This study aimed to investigate the effects of phage therapy and antibiotic therapy on memory function in rats with P. aeruginosa infected burn wounds.MethodsAdult male rats were divided into three groups: (1) infected without treatment (control), (2) infected and treated with colistin antibiotic (3,000,000 international units/kg/day), and (3) infected and treated with 100 μL of phage suspension (approximately 109 PFU/mL). In all animals, after anesthesia, a third‐degree burn was created in the back area. One hour later, treatment was performed for seven consecutive days. Passive avoidance test, novel object recognition test, locomotion activity, hippocampal neuron count, and oxidative stress measurement in blood serum were performed.ResultsIn antibiotic‐treated group memory recall, recognition index, number of healthy neurons in CA1, CA2, and CA3 hippocampus areas and the amounts of MDA, and FRAP significantly decreased compared with the control group. The phage‐treated group was not shown any harmful effect on the memory process, number of healthy hippocampal neurons, and showed more positive effects in blood serum examinations compared with the antibiotic group.ConclusionsPhage therapy could be a safe and effective alternative to antibiotics in the treatment of burn‐related infections.

show abstract

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

Cited by 10 publications

References 146 publications

Tau Deletion Prevents Cognitive Impairment and Mitochondrial Dysfunction Age Associated by a Mechanism Dependent on Cyclophilin-D

Tau Deletion Prevents Cognitive Impairment and Mitochondrial Dysfunction Age Associated by a Mechanism Dependent on Cyclophilin-D

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

New findings about comparing the effects of antibiotic therapy and phage therapy on memory and hippocampal pyramidal cells in rats

Contact Info

Product

Resources

About