Mitochondria-tau association promotes cognitive decline and hippocampal bioenergetic deficits during the aging
Autor
Olesen, Margrethe A.
Pradenas, Eugenia
Villavicencio-Tejo, Francisca
Porter, George A.
Johnson, Gail V.W.
Quintanilla, Rodrigo A.
Resumen
Current studies indicate that pathological modifications of tau are associated with mitochondrial dysfunction, synaptic failure, and cognitive decline in neurological disorders and aging. We previously showed that caspase-3 cleaved tau, a relevant tau form in Alzheimer's disease (AD), affects mitochondrial bioenergetics, dynamics and synaptic plasticity by the opening of mitochondrial permeability transition pore (mPTP). Also, genetic ablation of tau promotes mitochondrial function boost and increased cognitive capacities in aging mice. However, the mechanisms and relevance of these alterations for the cognitive and mitochondrial abnormalities during aging, which is the primary risk factor for AD, has not been explored. Therefore, in this study we used aging C57BL/6 mice (2–15 and 28-month-old) to evaluate hippocampus-dependent cognitive performance and mitochondrial function. Behavioral tests revealed that aged mice (15 and 28-month-old) showed a reduced cognitive performance compared to young mice (2 month). Concomitantly, isolated hippocampal mitochondria of aged mice showed a significant decrease in bioenergetic-related functions including increases in reactive oxygen species (ROS), mitochondrial depolarization, ATP decreases, and calcium handling defects. Importantly, full-length and caspase-3 cleaved tau were preferentially present in mitochondrial fractions of 15 and 28-month-old mice. Also, aged mice (15 and 28-month-old) showed an increase in cyclophilin D (CypD), the principal regulator of mPTP opening, and a decrease in Opa-1 mitochondrial localization, indicating a possible defect in mitochondrial dynamics. Importantly, we corroborated these findings in immortalized cortical neurons expressing mitochondrial targeted full-length (GFP-T4-OMP25) and caspase-3 cleaved tau (GFP-T4C3-OMP25) which resulted in increased ROS levels and mitochondrial fragmentation, along with a decrease in Opa-1 protein expression. These results suggest that tau associates with mitochondria and this binding increases during aging. This connection may contribute to defects in mitochondrial bioenergetics and dynamics which later may conduce to cognitive decline present during aging. © 2024 Elsevier Inc.
Colecciones
Ítems relacionados
Mostrando ítems relacionados por Título, autor o materia.
-
Article
The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders (2024)
Olesen, Margrethe A.; Villavicencio-Tejo, Francisca; Quintanilla, Rodrigo A. (BioMed Central Ltd, 2022)Neurological disorders (NDs) are characterized by progressive neuronal dysfunction leading to synaptic failure, cognitive impairment, and motor injury. Among these diseases, Alzheimer's disease (AD), Parkinson's disease ... -
Article
Activation of the Nrf2 Pathway Prevents Mitochondrial Dysfunction Induced by Caspase-3 Cleaved Tau: Implications for Alzheimer’s Disease (2022)
Villavicencio-Tejo, Francisca; Olesen, Margrethe A.; Aránguiz, Alejandra; Quintanilla, Rodrigo A. (MDPI, 2022-03)Alzheimer’s disease (AD) is characterized by memory and cognitive impairment, accom-panied by the accumulation of extracellular deposits of amyloid β-peptide (Aβ) and the presence of neurofibrillary tangles (NFTs) composed ... -
Article
Adolescent Binge Alcohol Exposure Affects the Brain Function Through Mitochondrial Impairment (2020)
Tapia-Rojas C.; Carvajal F.J.; Mira R.G.; Arce C.; Lerma-Cabrera J.M.; Orellana J.A.; Cerpa W.; Quintanilla R.A. (Humana Press Inc., 2018)