Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies?

Abstract

Hyperphosphorylation and aggregation of the microtubule-associated protein tau in brain, are pathological hallmarks of a large family of neurodegenerative disorders, named tauopathies, which include Alzheimer's disease. It has been shown that increased phosphorylation of tau destabilizes tau-microtubule interactions, leading to microtubule instability, transport defects along microtubules, and ultimately neuronal death. However, although mutations of the MAPT gene have been detected in familial early-onset tauopathies, causative events in the more frequent sporadic late-onset forms and relationships between tau hyperphosphorylation and neurodegeneration remain largely elusive. Oxidative stress is a further pathological hallmark of tauopathies, but its precise role in the disease process is poorly understood. Another open question is the source of reactive oxygen species, which induce oxidative stress in brain neurons. Mitochondria have been classically viewed as a major source for oxidative stress, but microglial cells were recently identified as reactive oxygen species producers in tauopathies. Here we review the complex relationships between tau pathology and oxidative stress, placing emphasis on (i) tau protein function, (ii) origin and consequences of reactive oxygen species production, and (iii) links between tau phosphorylation and oxidative stress. Further, we go on to discuss the hypothesis that tau hyperphosphorylation and oxidative stress are two key components of a vicious circle, crucial in neurodegenerative tauopathies.

Tau protein liquid–liquid phase separation can initiate tau aggregation

“…In the diseased brain, however, we postulate that conditions leading to aberrant tau hyperphosphorylation could favor the kinetics of droplet formation and stabilization—such as AD and FTD (Gong et al , 2005), elevated oxidative stress (Alavi Naini & Soussi‐Yanicostas, 2015), or traumatic brain injury (Blennow et al , 2012)—may favor the droplet state of tau, lead to increased droplet stability and droplet maturation, and eventually initiate tau aggregation. To what extent specific phosphorylation sites join this interplay of LLPS and aggregation remains to be explored.…”

LX2343 alleviates cognitive impairments in AD model rats by inhibiting oxidative stress-induced neuronal apoptosis and tauopathy

“…Therefore, the triple effects of LX2343 on neuroprotection, Aβ inhibition, and tau modulation indicate the potential of this multi-target compound in the treatment of AD. OS is a pivotal cellular response to the damage caused by tau toxicity, and the vicious interaction between these two causative events promotes AD progression [38] . Studies have identified OS as an early marker of tauopathy since OS and mitochondrial dysfunction are detected prior to tau hyperphosphorylation and NFT accumulation in tau P301S transgenic mice, which show tau hyperphosphorylation and tangle formation in 3 months [39] .…”

“…Studies have identified OS as an early marker of tauopathy since OS and mitochondrial dysfunction are detected prior to tau hyperphosphorylation and NFT accumulation in tau P301S transgenic mice, which show tau hyperphosphorylation and tangle formation in 3 months [39] . On the one hand, OS amplifies tauinduced neurotoxicity by induction of apoptosis and dysregulation of cell energy metabolism and promotes tau hyperphosphorylation and aggregation [38] . On the other hand, tauopathy induces OS [40] .…”

“…For example, vitamin E decreased ROS production and tau phosphorylation [22,46] and chronic administration of coenzyme Q10 to tau P301S mice alleviated ROS accumulation and tau hyperphosphorylation, thus improving behavioral deficits in the transgenic mice [40] . Although the results obtained using animal studies have suggested that antioxidants are potential therapeutic agents for the treatment of AD and tauopathy-relevant diseases, the translation of these inspiring results obtained in animal models into clinical use has not yet led to significant advances [38] . Therefore, new strategies are needed to design effective agents against OS or tauopathy to break the deadlock.…”

Oxidative Stress, Inflammation, and Formation of Beta‐ Amyloid 1‐42 in Brain

“…For their part, actin ilaments are less susceptible to the negative efects of oxidative stress because they use ROS for their reorganization [44]. Finally, neuroilaments are phosphorylated in the presence of reactive species, which causes the formation of protein aggregates as the ones found in neurodegenerative diseases like Alzheimer's [45].…”