Abstract

Synaptic failure and neurofibrillary degeneration are two major neuropathological substrates of cognitive dysfunction in Alzheimer’s disease (AD). Only a few studies have demonstrated a direct relationship between these two AD hallmarks. To investigate tau mediated synaptic injury we used rat model of tauopathy that develops extensive neurofibrillary pathology in the cortex. Using fractionation of cortical synapses, we identified an increase in endogenous rat tau isoforms in presynaptic compartment, and their mis-sorting to the postsynaptic density (PSD). Truncated transgenic tau was distributed in both compartments exhibiting specific phospho-pattern that was characteristic for each synaptic compartment. In the presynaptic compartment, truncated tau was associated with impairment of dynamic stability of microtubules which could be responsible for reduction of synaptic vesicles. In the PSD, truncated tau lowered the levels of neurofilaments. Truncated tau also significantly decreased the synaptic levels of Aβ40 but not Aβ42. These data show that truncated tau differentially deregulates synaptic proteome in pre- and postsynaptic compartments. Importantly, we show that alteration of Aβ can arise downstream of truncated tau pathology.

Highlights

  • Neurofibrillary tangles, amyloid plaques, neuronal loss and synaptic failure represent the major hallmarks of Alzheimer’s disease (AD; Wischik et al, 1988; Rinne et al, 1989; DeKosky and Scheff, 1990; Cras et al, 1991; West et al, 1994; Coleman and Yao, 2003)

  • Our findings suggest that truncated tau is a potent inducer of synaptic damage synapses independent of Aβ pathology

  • CORTICAL TAU NEUROFIBRILLARY PATHOLOGY IS A HALLMARK OF THE TRANSGENIC RAT MODEL OF HUMAN TAUOPATHY Sarkosyl insoluble tau is considered the proteomic correlate of the mature neurofibrillary degeneration

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Summary

Introduction

Neurofibrillary tangles, amyloid plaques, neuronal loss and synaptic failure represent the major hallmarks of Alzheimer’s disease (AD; Wischik et al, 1988; Rinne et al, 1989; DeKosky and Scheff, 1990; Cras et al, 1991; West et al, 1994; Coleman and Yao, 2003). Using pan tau antibody DC25, we observed an identical pattern of endogenous rat tau in soluble fractions, and an additional presence of human truncated tau in the transgenic animals (Figure 1A). Human truncated tau was distributed in both synaptic fractions in transgenic animals (Figures 2A,B).

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