Abnormal tau induces cognitive impairment through two different mechanisms: synaptic dysfunction and neuronal loss.

J Di,G R Phillips,L S Cohen,C P Corbo,A El Idrissi,A D Alonso

doi:10.1038/srep20833

Abstract

The hyperphosphorylated microtubule-associated protein tau is present in several neurodegenerative diseases, although the causal relationship remains elusive. Few mouse models used to study Alzheimer-like dementia target tau phosphorylation. We created an inducible pseudophosphorylated tau (Pathological Human Tau, PH-Tau) mouse model to study the effect of conformationally modified tau in vivo. Leaky expression resulted in two levels of PH-Tau: low basal level and higher upon induction (4% and 14% of the endogenous tau, respectively). Unexpectedly, low PH-Tau resulted in significant cognitive deficits, decrease in the number of synapses (seen by EM in the CA1 region), reduction of synaptic proteins, and localization to the nucleus. Induction of PH-Tau triggered neuronal death (60% in CA3), astrocytosis, and loss of the processes in CA1. These findings suggest, that phosphorylated tau is sufficient to induce neurodegeneration and that two different mechanisms can induce cognitive impairment depending on the levels of PH-Tau expression.

Highlights

In which 10 different sites on tau were pseudohyperphosphorylated was generated but no indications of neurodegeneration or differences in learning or memory were detected[23]
We have demonstrated that tau pseudophosphorylated at Thr[212], Thr[231] and Ser[262] mimics Alzheimer’s disease (AD) abnormal tau[29] and that tau pseudophosphorylated at Ser 199, Thr[212], Thr[231] and Ser[262] impairs learning and memory in Drosophila[30]
We have shown that when PH-tau was expressed in CHO cells it was aggregated in the cells, disrupted microtubules, and translocated in the nucleus[29]

Summary

Introduction

In which 10 different sites on tau were pseudohyperphosphorylated was generated but no indications of neurodegeneration or differences in learning or memory were detected[23]. We found that double transgenic mice in which PH-Tau is suppressed still expressed baseline levels of PH-Tau (~4% of total tau protein, PH-Taulow) At this low level, PH-Tau is detected as oligomers and its expression triggers early cognitive deficits which may be caused by loss of synapses in the hippocampus. PH-Tau is detected as oligomers and its expression triggers early cognitive deficits which may be caused by loss of synapses in the hippocampus These cognitive deficits appear to be more significant than in the mice in which expression of PH-Tau is induced (see below). To our knowledge, this is the first model where barely detectable levels of abnormal tau can cause dramatic effects. We believe this is the first evidence of two different mechanisms leading to cognitive decline that may be the result of varying levels of PH-Tau expression

Methods

Results

Conclusion