cis pT231-Tau Drives Neurodegeneration in Bipolar Disorder

Abstract

Bipolar disorder is a complex neuropsychiatric disorder, characterized by intermittent episodes of mania and depression. Recent studies have indicated argyrophilic grains, composed of hyperphosphorylated tau, are observable in postmortem brains of bipolar patients. It remains uncertain how tau hyperphosphorylation results in neurodegeneration upon the disease. Recent studies have demonstrated that phosphorylated tau at Thr231 exists in two distinct cis and trans conformations, in which cis pT231-tau is highly neurotoxic and acts as an early driver of tauopathy in several neurodegenerative diseases. We herein employed an in vitro model, which resembles some aspects of bipolar disorder, to study the cis p-tau mediatory role. We established GSK3β overexpressing SH-SY5Y cells and examined cell viability, cis p-tau formation, and lithium effects by immunofluorescence and flow cytometry. We found an increase in cis p-tau levels as well as viability decrease in the cell model. Furthermore, we discovered that lithium treatment inhibits cis p-tau formation, resulting in diminished cell death. We also examined BD and healthy human brain samples and detected cis p-tau in the patients’ brains. Our results show that tauopathy, observed in bipolar disorder, is being mediated through cis p-tau and that a conformer could be the cause of neurodegeneration upon the disease. Our findings would suggest novel therapeutic target to fight the devastating disorder.

Key Disease Mechanisms Linked to Alzheimer’s Disease in the Entorhinal Cortex

“…Deficits in the electron transport chain complex proteins I and IV, NADH dehydrogenase and c-oxidase, respectively, were dysregulated in both AD and bipolar disorder, along with a host of other neuropsychiatric complications. Examination of postmortem brains of individuals afflicted with bipolar disorder revealed tangles composed of hyperphosphorylated tau and subsequent neurodegeneration similar to AD pathology [99]. Administration of the commonly used drug for bipolar disorder lithium decreased cis phosphorylated tau levels and reduced subsequent neurodegeneration, suggesting a potential therapeutic option for bipolar disorder and AD [99].…”

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…Examination of bipolar and healthy human brain samples also detected cis p-tau in the patients' brains. 525 Antibodies have been developed to specifically recognize this unique phosphor-epitope in tau. The Configuration specific antibodies were developed to distinguish cis-and trans-tau.…”

α‐synuclein abnormalities trigger focal tau pathology, spreading to various brain areas in Parkinson disease

“…We herein examined the causative link between P‐α‐synuclein and P‐tau employing various strategies. Recent studies have shown that cis pT231‐tau appears earlier than tau tangles (Albayram et al., 2017; Kondo et al., 2015; Naserkhaki et al., 2019). Consistent with previous findings, we demonstrated that cis pT231‐tau appeared earlier than tau tangles with PD in the in vitro and in vivo systems.…”

“…Up until now, the pathogenic P‐tau species have been detectable only at very late stages, whose removal is too late to retrieve neuronal functions (Chesser et al., 2013; Pedersen & Sigurdsson, 2015; Sigurdsson, 2008). Finally, cis pT231‐tau was recently introduced as an early driver of the tauopathy process upon traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), AD, and Bipolar disorder (Albayram et al., 2017; Farhadi et al., 2019; Kondo et al., 2015; Naserkhaki et al., 2019). In this study, we examined various pathogenic markers to demonstrate the correlation between α‐synuclein and tau pathology and propose an efficient therapeutic strategy in the early stages of PD.…”