Aging is a natural and multifactorial process mediated by physiological, genetic, and biological changes that could increase susceptibility to numerous diseases (Z [1]). Aging is considered a primary risk factor for the development of several neurodegenerative diseases, including sporadic AD (Z [1]). During aging, synaptic abnormalities in hippocampal neurons contribute to cognitive impairment in human patients [2]. Importantly, aged mouse models mimic hippocampus deficiencies observed in human patients, including memory loss and cognitive decline [[3], [4], [5], [6]]. These cognitive abnormalities have been accompanied by the presence of mitochondrial dysfunction, suggesting an essential role of this organelle in this neurodegenerative process [5,7,8].

Mitochondria are organelles essential for neuronal function, supplying energy, regulating calcium levels, and producing reactive oxidative species (ROS) such as superoxide anion (O2−), hydrogen peroxide (H2O2), and hydroxyl radicals (−OH) [8]. In this context, aging-related mitochondrial abnormalities include a reduced mitochondrial respiratory capacity [7], mitochondrial depolarization, ATP loss [9], increased ROS levels [9], and mitochondrial calcium handling defects [10]. Nevertheless, how brain mitochondria damage is triggered during aging is still not completely understood.

Tau protein is a microtubule-associated protein (MAP) predominantly expressed in neurons that modulates microtubule polymerization, (reviewed in [11,12]), synaptic plasticity, and transport of lipids, proteins, and organelles such as mitochondria ([13,14]; reviewed by [15]). In the last decades, the study of tau has gained significant attention since reports have indicated that intraneuronal accumulation of soluble toxic tau forms is considered a hallmark of neurological disorders called tauopathies [15,16]. For example, studies have demonstrated that tau overexpression promotes hippocampal neurodegeneration which progresses in an age-dependent manner [[17], [18], [19]]. Moreover, tau aggregation has been observed in the hippocampus and the temporal lobe of aged human brain samples [20]. Importantly, several studies have suggested that pathological forms of tau contribute to these neurodegenerative processes in part by altering the association of tau with different organelles ([[21], [22], [23]]S. [[24], [25], [26], [27], [28]]).

In this context, caspase-3 cleaved tau, a pathological tau form produced by truncation at Asp421 by caspase-3, that contributes to neurofibrillary tangles (NFT) formation [29], plays a relevant role in mitochondrial dysfunction and synaptic plasticity defects present in AD [28,30,31]. Expression of this tau form induces mitochondrial impairment (depolarization, ROS increase, and ATP loss and affects synaptic function decreasing dendritic spines density, reducing recycling vesicles number, and modifying synaptophysin function in hippocampal neurons [31]. Also, caspase-3 cleaved tau showed a preferential association with mitochondrial permeability transition pore (mPTP) protein components (cyclophilin D and OSCP) increasing mPTP opening and mitochondrial permeability, thus affecting mitochondrial function [28]. However, the contribution of caspase-3 cleaved tau in mitochondrial failure and cognitive decline present during the aging have not been addressed.

In this study, we examined the participation of tau, and its pathological form, caspase-3 cleaved tau in cognitive decline and impaired mitochondrial function during aging. First, we observed that aged animals (15 and 28-month-old mice) showed a significant loss in cognitive capacities compared to young mice (2-months). Interestingly, we found that full-length tau protein was accumulated in the mitochondrial fraction in an age-dependent manner (15 and 28-month-old mice), which was accompanied with an impairing of mitochondrial bioenergetics and dynamics in the hippocampus. More importantly, caspase-3 cleaved tau was found to be increased in the mitochondrial fraction of 15 and 28-month-old mice.

To complement these findings, in neuronal cells, we directed the expression of full-length and caspase-3 cleaved tau to mitochondria using tau constructs tagged with a GFP fusion protein with outer-mitochondrial protein 25 (GFP-OMP25). Mitochondrially targeted full-length and caspase-3 cleaved tau mimicked the increase in ROS, and mitochondrial dynamics defects observed in aged mice (15 and 28-month-old), generating mitochondrial fragmentation concurrent with a decrease in Opa-1 expression.