Abstract
Microtubule associated protein tau (tau) deposition is associated with a spectrum of neurodegenerative diseases collectively termed tauopathies. We have previously shown that amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) is associated with tau phosphorylation at Thr175 and that this leads to activation of GSK3β which then induces phosphorylation at tau Thr231. This latter step leads to dissociation of tau from microtubules and pathological tau fibril formation. To determine the extent to which this pathway is unique to ALS, we have investigated the expression of pThr175 tau and pThr231 tau across a range of frontotemporal degenerations. Representative sections from the superior frontal cortex, anterior cingulate cortex (ACC), amygdala, hippocampal formation, basal ganglia, and substantia nigra were selected from neuropathologically confirmed cases of Alzheimer’s disease (AD; n = 3), vascular dementia (n = 2), frontotemporal lobar degeneration (FTLD; n = 4), ALS (n = 5), ALSci (n = 6), Parkinson’s disease (PD; n = 5), corticobasal degeneration (CBD; n = 2), diffuse Lewy body dementia (DLBD; n = 2), mixed DLBD (n = 3), multisystem atrophy (MSA; n = 6) and Pick’s disease (n = 1) and three neuropathologically-normal control groups aged 50–60 (n = 6), 60–70 (n = 6) and 70–80 (n = 8). Sections were examined using a panel of phospho-tau antibodies (pSer208,210, pThr217, pThr175, pThr231, pSer202 and T22 (oligomeric tau)). Across diseases, phospho-tau load was most prominent in layers II/III of the entorhinal cortex, amygdala and hippocampus. This is in contrast to the preferential deposition of phospho-tau in the ACC and frontal cortex in ALSci. Controls showed pThr175 tau expression only in the 7th decade of life and only in the presence of tau pathology and tau oligomers. With the exception of DLBD, we observed pThr175 co-localizing with pThr231 in the same cell populations as T22 positivity. This suggests that this pathway may be a common mechanism of toxicity across the tauopathies.
Highlights
Microtubule associated protein tau is a cytoskeletal stabilizing protein involved in microtubule maintenance, fast axonal transport, and other physiological functions in neurons
Unlike other widely accepted pathological phosphorylation sites on tau, such as pThr231 and pSer202, pThr175 has not been observed in the fetal brain where tau protein is hyperphosphorylated [14,15,16], suggesting that this site may be uniquely associated with pathological processes. pThr175 tau has been shown to induce GSK3β activation in cell culture and may act as a destabilizing event resulting in enhanced phosphorylation of tau at other residues, resulting in dissociation from microtubules and neuronal toxicity [17]
amyotrophic lateral sclerosis with cognitive impairment (ALSci) Tau pathology (Fig. 1, Additional file 1: Figure S1, Additional file 2: Figure S2, Additional file 3: Figure S3) in the form of tangles, skein-like inclusions, and punctate staining was observed to a greater extent in ALSci than amyotrophic lateral sclerosis (ALS), especially in the anterior cingulate cortex (ACC) and superior frontal cortex
Summary
Microtubule associated protein tau (tau) is a cytoskeletal stabilizing protein involved in microtubule maintenance, fast axonal transport, and other physiological functions in neurons. It has been shown that pathological species of tau protein are abnormally phosphorylated at multiple. First identified in Alzheimer’s disease as a unique phosphoepitope [5], it was determined that this site could be phosphorylated by multiple kinases linked to tau protein pathology, including GSK3β, JNK, ERK2, and p38 [6]. PThr175 tau has been shown to induce tau fibril formation and cell death in vitro [13]. PThr175 tau has been shown to induce GSK3β activation in cell culture and may act as a destabilizing event resulting in enhanced phosphorylation of tau at other residues, resulting in dissociation from microtubules and neuronal toxicity [17]. In order to understand the extent to which this pathway of pThr175 mediated tau aggregate formation underlies a broad range of tauopathies, we have used a panel of phospho-specific antibodies to characterize tau protein pathology with specific interest in the expression of pThr175 tau across a broad range of tauopathies
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