Alzheimer's disease (AD) is a severe progressive neurodegenerative condition associated with neuronal damage and reduced cognitive function that primarily affects the aged worldwide. While there is increasing evidence suggesting that mitochondrial dysfunction is one of the most significant factors contributing to AD, its accurate pathobiology remains unclear. Mitochondrial bioenergetics and homeostasis are impaired and defected during AD pathogenesis. However, the potential of mutations in nuclear or mitochondrial DNA encoding mitochondrial constituents to cause mitochondrial dysfunction has been considered since it is one of the intracellular processes commonly compromised in early AD stages. Additionally, electron transport chain dysfunction and mitochondrial pathological protein interactions are related to mitochondrial dysfunction in AD. Many mitochondrial parameters decline during aging, causing an imbalance in reactive oxygen species (ROS) production, leading to oxidative stress in age-related AD. Moreover, neuroinflammation is another potential causative factor in AD-associated mitochondrial dysfunction. While several treatments targeting mitochondrial dysfunction have undergone preclinical studies, few have been successful in clinical trials. Therefore, this review discusses the molecular mechanisms and different therapeutic approaches for correcting mitochondrial dysfunction in AD, which have the potential to advance the future development of novel drug-based AD interventions.
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http://dx.doi.org/10.2174/1570159X22666240426091311 | DOI Listing |
Liver Transpl
October 2024
Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
Hypothermic oxygenated machine perfusion (HOPE) preconditions liver grafts before transplantation. While beneficial effects on patient outcomes were demonstrated, biomarkers for viability assessment during HOPE are scarce and lack validation. This study aims to validate the predictive potential of perfusate flavin mononucleotide (FMN) during HOPE to enable the implementation of FMN-based assessment into clinical routine and to identify safe organ acceptance thresholds.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
Background: The mitochondrial cascade hypothesis suggests that mitochondrial dysfunction plays an important role in the pathogenesis of Alzheimer's disease dementia. Recent data have shown that mitochondrial DNA copy number (mtDNAcn) in human blood is associated with dementia risk and cognitive function, but which specific cognitive measures or domains are associated with mitochondrial dysfunction and whether this relationship is affected by health deterioration such as physical frailty or mitochondrial somatic mutations is not clear.
Methods: We measured mtDNAcn and heteroplasmies using fastMitoCalc and MitoCaller, respectively, from UK Biobank Whole Genome Sequencing (WGS) data at study entry (2006-2010).
Alzheimers Dement
December 2024
University of California, Los Angeles Integrative Biology and Physiology (IBP), Los Angeles, CA, USA.
Background: APOE is in linkage disequilibrium with the length of poly-T repeats at the rs10524523 ('523) locus of the TOMM40 gene. APOE-ε3 is associated with short (S) and (VL) variants of '523 in white and Black individuals. In white individuals, APOE-ε4 is associated with the long (L) '523 variant, but is associated with '523-S, '523-L, and '523-VL variants in Black individuals.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Huntington Medical Research Institutes, Pasadena, CA, USA.
Background: Dicarboxylic acids (DCAs) are critically important for intermediate metabolism. Since mitochondrial dysfunction and energy dysregulation are associated with AD pathology, we hypothesize that fluctuations in plasma DCAs would accompany AD pathology.
Method: In an ongoing brain-aging study, we recruited older adults (>65 years) classified as cognitively healthy (CH) after neuropsychological testing.
Background: Two main risk factors of Alzheimer's disease (AD) are aging and APOE-ε4. However, some individuals remain cognitively normal despite having these risk factors. They are considered "cognitively resilient".
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