Mitochondria modulatory effects of new TSPO ligands in a cellular model of tauopathies

Abstract

Translocator protein 18 kDa (TSPO) is a mitochondrial protein located in the outer membrane and involved in cholesterol translocation, a prerequisite for steroid biosynthesis. TSPO modulation also appears to play a role in other mitochondrial functions, including mitochondrial respiration and cell survival. In the central nervous system, its expression is up‐regulated in neuropathology such as Alzheimer's disease (AD). Previously, we demonstrated that two new TSPO ligands, named 2a and 2b, stimulated pregnenolone synthesis and ATP production in a cellular model of AD overproducing β‐amyloid peptide. The present study aimed to evaluate the impact of the new TSPO ligands on mitochondrial dysfunction in a cellular model of AD‐related tauopathy (human neuroblastoma cells SH‐SY5Y stably overexpressing the P301L‐mutant Tau) presenting mitochondrial impairments, including a decreased ATP synthesis and mitochondrial membrane potential, as well as a decrease in pregnenolone synthesis compared to control cells. The effects of our new ligands were compared with those of TSPO ligands described in the literature (XBD173, SSR‐180,575 and Ro5‐4864). The TSPO ligands 2a and 2b exerted beneficial mitochondrial modulatory effects by increasing ATP levels and mitochondrial membrane potential, paralleled by an increase of pregnenolone levels in mutant Tau cells, as well as in control cells. The compounds 2a and 2b showed effects on mitochondrial activity similar to those obtained with the TSPO ligands of reference. These findings indicate that the new TSPO ligands modulate the mitochondrial bioenergetic phenotype as well as the de novo synthesis of neurosteroids in a cellular model of AD‐related tauopathy, suggesting that these compounds could be potential new therapeutic tools for the treatment of AD.

Clock-Controlled Mitochondrial Dynamics Correlates with Cyclic Pregnenolone Synthesis

“…Neurosteroids are also able to modulate neuronal bioenergetics by increasing mitochondrial respiration and ATP production, at least in part via nuclear steroid receptor activation [ 36 ]. Our recent findings revealed that the P5 levels were decreased in cellular models of AD, together with impairments in mitochondrial bioenergetics [ 37 , 38 ]. Strikingly, treatment with TSPO ligands increased P5 production and improved mitochondrial energy production in the presence of AD-related pathological proteins, amyloid-β peptide, and abnormal Tau protein.…”

The Translocator Protein (TSPO) in Mitochondrial Bioenergetics and Immune Processes

“…These ligands could also stabilise mitochondrial respiration under stress conditions, and ultimately reduce levels of amyloid beta formation [64]. These novel ligands have also been found to increase levels of ATP production and stabilise mitochondrial membrane potential unrelated to any effects on steroidogenesis [65]. TSPO ligands have also demonstrated analogous effects in other immune cell types, as PK11195 was shown to reduce basal ROS generation in mouse primary peritoneal macrophages [66], and Ro5-4864 has been shown to preserve mitochondrial membrane potential and reduce ROS production after glucose deprivation stress in astrocytes, compared to controls [67].…”

Insights into Disease-Associated Tau Impact on Mitochondria

“…In particular, phospho-tau interaction with VDAC was evident in the brain of AD patients at different Braak stages (I to V), as well as in 13-months-old APP/PS1 and 3xTgAD transgenic mice [ 145 ]. Furthermore, in our recent study, we showed that TSPO ligands increased the ΔΨm in htau- and P301L tau-overexpressing SH-SY5Y cells [ 131 ]. We speculated that this effect was mediated by the ability of these ligands to modulate the mPTP, although further investigations need to be conducted to determine the exact underlying mechanisms.…”

“…We recently showed that abnormal tau also disturbs another mitochondrial function: the synthesis of neurosteroids or neurosteroidogenesis [ 131 ]. Indeed, steroids can be synthesized de novo in the brain from cholesterol, independently of the peripheral steroidogenic glands, and are then called “neuro”-steroids (reviewed in [ 148 ]).…”

“…In our recent study, we showed that PREG levels were decreased in htau-overexpressing SH-SY5Y cells, and even more significantly reduced in P301L cells [ 131 ]. This effect was normalized in cells treated with TSPO ligands, which is involved in the first step of neurosteroidogenesis in mitochondria.…”