Widespread neuronal and glial hyperphosphorylated tau deposition in ALS with cognitive impairment.

Although the biological basis of frontotemporal syndromes associated with amyotrophic lateral sclerosis (ALS) is considered to be altered metabolism of TDP-43, in ALS with cognitive impairment (ALSci) the metabolism of tau protein is also altered. This includes neuronal hyperphosphorylation (pThr(175)). Using novel polyclonal phospho-tau antibodies (pSer(208, 210), pThr(217) and pThr(175)) and antibodies directed against PHF tau (pSer(202)), TDP-43 or ubiquitin, we characterized tau deposition in ALS and ALSci. In ALS, we observed pThr(175) tau immunoreactive intraneuronal and neuritic aggregates throughout the amygdala and entorhinal cortex. In ALSci, this extended to the anterior cingulate gyrus, superior frontal cortex and substantia nigra. The pThr(217) antibody detected widespread astrocytic tau deposition, including punctuate or fibrillary aggregates, or intensely immunoreactive tufted astrocytes in the superior frontal cortex, anterior cingulate gyrus, entorhinal cortex, amygdala and basal ganglia of ALS. In ALSci, a similar but more widely distributed pThr(217) pathology was observed. There was no correlation between the extent of pathological tau deposition and TDP-43 pathology, although nuclear TDP-43 immunoreactivity was absent in neurons with tau pathology. In conclusion, ALSci is unique in possessing both tau and TDP-43 pathology. The presence of widespread astrocytic tau pathology suggests that ALSci may initially be characterized by astrocytic pathology.