Differential accumulation of Tau phosphorylated at residues Thr231, Ser262 and Thr205 in hippocampal interneurons and its modulation by Tau mutations (VLW) and amyloid-β peptide

Abstract

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β peptide (Aβ) and hyperphosphorylated Tau protein (P-Tau). Our recent data showed a differential accumulation of Tau protein phosphorylated at residue Thr231 (pThr231) in distinct hippocampal neurons in VLW mice-a model that overexpresses mutated human Tau. Here we demonstrate that, in VLW mice, the accumulation of human P-Tau in pyramidal cells induces the phosphorylation of murine Tau at residue Thr231 in hippocampal interneurons. In addition, we show that pSer262 and pThr205 Tau are present specifically in the soma of some hippocampal interneurons in control mice. Analysis of J20 mice-a model that accumulates Aβ-and of VLW animals showed that the density of hippocampal interneurons accumulating pThr205 Tau is lower in VLW mice than in controls. In contrast, the density of interneurons accumulating pThr205 Tau in J20 mice was increased compared to controls in hippocampal regions with a higher Aβ plaque load, thereby suggesting that pThr205 Tau is induced by Aβ. No significant differences were found between the density of hippocampal interneurons positive for pSer262 Tau in VLW or J20 mice compared to control animals. We also show that pSer262 and pThr205 Tau are present in the soma of some hippocampal interneurons containing Parvalbumin, Calbindin or Calretinin in control, VLW, and J20 mice. Moreover, our results reveal that some interneurons in human hippocampi of cases of AD and control cases accumulate pSer262 and pThr205 Tau. Taken together, these data point to a specific role of pSer262 and pThr205 Tau in the soma of hippocampal interneurons in control and pathological conditions.

Keywords: Alzheimer's disease; Frontotemporal dementia with parkinsonism linked to chromosome 17; GABAergic neurons; J20 mice; Tau phosphorylation; VLW mice.