Abstract
Mitochondria are highly specialized organelles essential for the synapse, and their impairment contributes to the neurodegeneration in Alzheimer’s disease (AD). Previously, we studied the role of caspase-3–cleaved tau in mitochondrial dysfunction in AD. In neurons, the presence of this AD-relevant tau form induced mitochondrial fragmentation with a concomitant reduction in the expression of Opa1, a mitochondrial fission regulator. More importantly, we showed that caspase-cleaved tau affects mitochondrial transport, decreasing the number of moving mitochondria in the neuronal processes without affecting their velocity rate. However, the molecular mechanisms involved in these events are unknown. We studied the possible role of motor proteins (kinesin 1 and dynein) and mitochondrial protein adaptors (RhoT1/T2, syntaphilin, and TRAK2) in the mitochondrial transport failure induced by caspase-cleaved tau. We expressed green fluorescent protein (GFP), GFP-full-length, and GPF-caspase-3–cleaved tau proteins in rat hippocampal neurons and immortalized cortical neurons (CN 1.4) and analyzed the expression and localization of these proteins involved in mitochondrial transport regulation. We observed that hippocampal neurons expressing caspase-cleaved tau showed a significant accumulation of a mitochondrial population in the soma. These changes were accompanied by evident mitochondrial bioenergetic deficits, including depolarization, oxidative stress, and a significant reduction in ATP production. More critically, caspase-cleaved tau significantly decreased the expression of TRAK2 in immortalized and primary hippocampal neurons without affecting RhoT1/T2 and syntaphilin levels. Also, when we analyzed the expression of motor proteins—Kinesin 1 (KIF5) and Dynein—we did not detect changes in their expression, localization, and binding to the mitochondria. Interestingly, the expression of truncated tau significantly increases the association of TRAK2 with mitochondria compared with neuronal cells expressing full-length tau. Altogether these results indicate that caspase-cleaved tau may affect mitochondrial transport through the increase of TRAK2–mitochondria binding and reduction of ATP production available for the process of movement of these organelles. These observations are novel and represent a set of exciting findings whereby tau pathology could affect mitochondrial distribution in neurons, an event that may contribute to synaptic failure observed in AD.
Highlights
Mitochondria are the mastermind organelles in charge of energy production, calcium regulation, and antioxidant defenses
We observed that expression of truncated tau reduced the number of mitochondria present in neuronal processes compared with neurons transfected with full-length tau (GFP-T4) and green fluorescent protein (GFP)
Tau is a microtubule-associated protein (MAP) that interacts with microtubules, and nonphysiological modifications of tau could cause a destabilization of microtubular elements contributing to neurodegeneration in Alzheimer’s disease (AD) (Tapia-Rojas et al, 2019)
Summary
Mitochondria are the mastermind organelles in charge of energy production, calcium regulation, and antioxidant defenses (reviewed in Pérez et al, 2018a). Tau is a neuronal protein involved in the stabilization of microtubules, and its pathological modifications can affect neuronal function, including axonal transport (Quinn et al, 2018; Tapia-Rojas et al, 2019) In this context, the genetic reduction of tau expression prevented the impairment of mitochondrial transport induced by the treatment of hippocampal neurons with Aβ peptide (Vossel et al, 2010, 2015). The presence of a pathological tau modification such as hyperphosphorylation reduced mitochondrial transport through the axon (RodríguezMartín et al, 2013) by a mechanism that involved the impairment of different motor proteins (Shahpasand et al, 2012). These findings indicate that tau could be a vital element involved in the regulation of mitochondrial transport in neurons
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