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.
Spinal cord injury (SCI) can lead to neurological impairment with significant functional and cognitive deficits. It is obvious that SCI causes focal neurodegeneration that gradually expands to the other cord areas. On the other hand, it is clear that traumatic brain injuries result in tau protein pathology and profound neurodegeneration. Tau is a microtubule-associated protein, which is highly expressed in neurons, and its abnormalities result in neuronal cell death. Moreover, it is clear that tau pathology spreads in various brain areas upon trauma. Therefore, we herein examined tau pathology in the spinal cord as well as brain samples at various time-points in severe SCI mouse models. We examined the effects of severe SCI on locomotor function, spatial memory, and anxiety/risk-taking behavior. We found a gradual increased tau pathology in the spinal cord as well as brain areas; confirmed by immunostaining and immunoblotting. Moreover, we studied the brain samples with electron microscopy and observed disrupted mitochondria and microtubule structure upon SCI. SCI caused motor dysfunction, memory impairment, and abnormal risk-taking behavior. Importantly, pathogenic cis P-tau elimination with systemic administration of respective monoclonal antibody restored SCI-related pathological and functional consequences. Thus, our finding suggests that SCI results in profound tauopathy, which spreads to brain areas, reflecting brain dysfunction. Moreover, tau immunotherapy with anti-cis P-tau antibody could suppress the pathogenic outcomes in the SCI mouse models, which would have profound clinical implications in the SCI patients.
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