The Role of Mitochondrial Impairment in Alzheimer´s Disease Neurodegeneration: The Tau Connection

Abstract

Accumulative evidence has shown that mitochondrial dysfunction plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial impairment actively contributes to the synaptic and cognitive failure that characterizes AD. The presence of soluble pathological forms of tau like hyperphosphorylated at Ser396 and Ser404 and cleaved at Asp421 by caspase 3, negatively impacts mitochondrial bioenergetics, transport, and morphology in neurons. These adverse effects against mitochondria health will contribute to the synaptic impairment and cognitive decline in AD. Current studies suggest that mitochondrial failure induced by pathological tau forms is likely the result of the opening of the mitochondrial permeability transition pore (mPTP). mPTP is a mitochondrial mega-channel that is activated by increases in calcium and is associated with mitochondrial stress and apoptosis. This structure is composed of different proteins, where Ciclophilin D (CypD) is considered to be the primary mediator of mPTP activation. Also, new studies suggest that mPTP contributes to Aβ pathology and oxidative stress in AD. Further, inhibition of mPTP through the reduction of CypD expression prevents cognitive and synaptic impairment in AD mouse models. More importantly, tau protein contributes to the physiological regulation of mitochondria through the opening/interaction with mPTP in hippocampal neurons. Therefore, in this paper, we will discuss evidence that suggests an important role of pathological forms of tau against mitochondrial health. Also, we will discuss the possible role of mPTP in the mitochondrial impairment produced by the presence of tau pathology and its impact on synaptic function present in AD.

Keywords: Alzheimer´s disease; Mitochondria; Tau; calcium; mitochondrial permeability transition pore; oxidative stress.

Fig. (1)

Schematic representation of how tau protein can be pathologically modified by the action of different stressors in Alzheimer´s disease (AD). (a) Reactive oxygen species (ROS), (b) Amyloid-β peptide (Aβ), (c) Calcium (Ca²⁺) stress, and, (d) Aging. 1) As a result of several stressors, tau can be abnormally hyperphosphorylated at residues Ser396 and Ser404 and cleaved by the action of caspase-3 at D421 residue. These modifications can also affect mitochondrial health, and these actions could impact neuronal communication through synaptic impairment. (A higher resolution/colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Effects of hyperphosphorylated tau against mitochondria function. The presence of tau modifications like hyperphosphorylation (p-Tau) increases ROS levels, which could affect cardiolipin, a mitochondrial membrane phospholipid, increasing its oxidation. This modification may contribute to increasing the sensitivity of mitochondrial permeability transition pore (mPTP) to calcium and then produces its opening (1). Interestingly, it has been proposed that the presence of p-Tau in neurofibrillary tangles from AD patients interacts with voltage-dependent anion channel (VDAC), which is an important protein component of mPTP, producing a sustained opening state of the mPTP (2). The opening of mPTP impairs mitochondrial health inducing ROS production, mitochondrial membrane potential (MMP) loss, ATP reduction, and mitochondrial calcium handling defects (3). (A higher resolution/colour version of this figure is available in the electronic copy of the article).

Fig. (3)

Effects of truncated tau by caspase 3 (TauC3) against mitochondria health. The presence of TauC3 through the stressors agents could increase ROS levels affecting cardiolipin function and then sensitizes the mPTP opening to calcium. High ROS levels can also induced a sustained opening of the mPTP (1). mPTP opening will impair different aspects of mitochondrial health, including ROS production, mitochondrial membrane potential (MMP), ATP production, and mitochondrial calcium regulation (2). We showed that truncated tau expression induces mitochondrial fragmentation through the reduction in Opa1 levels in neuronal cells [19]. However, it is not clear if activation of mPTP would be involved in the reduction of mitochondrial length induced by truncated tau (3). Defects in mitochondrial bioenergetics produced by TauC3 can be prevented using cyclosporine A (CsA), an immunosuppressive drug that inhibits mPTP opening (4). Interestingly, other mitochondrial components like Appoptosin, a mitochondrial carrier protein for glycine, which expression increases TauC3, can also be involved in mitochondrial dysfunction and mPTP activation induced by TauC3 in the brain (5). (A higher resolution/colour version of this figure is available in the electronic copy of the article).