Contribution of Tau Pathology to Mitochondrial Impairment in Neurodegeneration

Abstract

Tau is an essential protein that physiologically promotes the assembly and stabilization of microtubules, and participates in neuronal development, axonal transport, and neuronal polarity. However, in a number of neurodegenerative diseases, including Alzheimer's disease (AD), tau undergoes pathological modifications in which soluble tau assembles into insoluble filaments, leading to synaptic failure and neurodegeneration. Mitochondria are responsible for energy supply, detoxification, and communication in brain cells, and important evidence suggests that mitochondrial failure could have a pivotal role in the pathogenesis of AD. In this context, our group and others investigated the negative effects of tau pathology on specific neuronal functions. In particular, we observed that the presence of these tau forms could affect mitochondrial function at three different levels: (i) mitochondrial transport, (ii) morphology, and (iii) bioenergetics. Therefore, mitochondrial dysfunction mediated by anomalous tau modifications represents a novel mechanism by which these forms contribute to the pathogenesis of AD. In this review, we will discuss the main results reported on pathological tau modifications and their effects on mitochondrial function and their importance for the synaptic communication and neurodegeneration.

Keywords: Alzheimer’s disease; mitochondria; synapse neurodegeneration; synapsis; tau.

FIGURE 1

Tau pathology impairs mitochondrial transport. In different cells and animal models, it has been described that hyperphosphorylated and truncated tau generate an increase in stationary mitochondria. Moreover, studies using different tau pathology models show an increase in the intermicrotubular distance that could be responsible for the mitochondrial movement reduction. At the same time, neuronal models that express pathological forms of tau show a decrease in anterograde transport and an increase in retrograde transport, which finally leads to an increase in perinuclear mitochondria.

FIGURE 2

Pathological forms of tau affect mitochondrial dynamics. In neurodegenerative diseases, the accumulation of pathological forms of tau (hyperphosphorylated and cleaved) impairs the regulation of mitochondrial dynamics. The overexpression of phosphorylated tau generates an increase in mitochondrial length, a decrease in fission proteins, and an increase in DRP1 mislocalization. Interestingly, tau phosphorylation increases endoplasmic reticulum-mitochondria contacts promoting a close interaction between tau, DRP1, and ER. On the other hand, C-terminal caspase-cleaved tau induces mitochondrial fragmentation through the reduction of the Opa1 expression. In addition, the presence of truncated tau at N-end increases the Parkin recruitment to the mitochondria, triggering an inappropriate and excessive autophagy.

FIGURE 3

Tau pathology affects mitochondrial bioenergetics in AD. Mitochondrial bioenergetics is significantly affected by tau pathology in AD. Phosphorylated and truncated tau severely affects mitochondrial membrane potential (MMP) and induces oxidative stress, which finally increases the mitochondrial sensibility to different stressors, such as Aβ and calcium. Moreover, phosphorylated tau decreases the expression of complex I and V, with a concomitant reduction in complex I activity and ATP production. In addition, caspase-cleaved tau impairs mitochondrial function affecting the calcium buffering capacity. Both pathological forms of tau present dysfunctional characteristics that suggest the involvement of the mitochondrial permeability transition pore (mPTP) in the bioenergetics failure. Phosphorylated tau induces an increase in VDAC/Tau interaction, and N-end truncated tau promotes an increase in ANT/CypD/Tau binding.