Abstract

The brain pathology of Alzheimer’s disease (AD) is characterized by the misfolding and aggregation of both the amyloid beta (Aβ) peptide and hyperphosphorylated forms of the tau protein. Initial Aβ deposition is considered to trigger a sequence of deleterious events contributing to tau pathology, neuroinflammation and ultimately causing the loss of synapses and neurons. To assess the effect of anti-Aβ immunization in this context, we generated a mouse model by overexpressing the human tau protein in the hippocampus of 5xFAD mice. Aβ plaque deposition combined with human tau overexpression leads to an array of pathological manifestations including the formation of tau-positive dystrophic neurites and accumulation of hyperphosphorylated tau at the level of neuritic plaques. Remarkably, the presence of human tau reduces microglial clustering in proximity to the Aβ plaques, which may affect the barrier role of microglia. In this mouse model, continuous administration of anti-Aβ antibodies enhances the clustering of microglial cells even in the presence of tau. Anti-Aβ immunization increases plaque compaction, reduces the spread of tau in the hippocampal formation and prevents the formation of tau-positive dystrophic neurites. However, the treatment does not significantly reduce tau-induced neurodegeneration in the dentate gyrus. These results highlight that anti-Aβ immunization is able to enhance microglial activity around neuritic plaques, mitigating part of the tau-induced pathological manifestations.

Highlights

  • In the absence of any disease-modifying treatment, Alzheimer’s disease (AD) leads to the progressive loss of memory and other cognitive functions

  • Unilateral injection of AAV‐tau in the Cornu Ammonis areas 3 (CA3) hippocampus of 5xFAD mice to generate a model of amyloid beta (Aβ)/tau pathology In order to assess the interaction between the Aβ and tau pathologies in vivo, we developed a mouse model based on the unilateral intrahippocampal injection of a serotype 8 adeno-associated viral (AAV8) vector encoding the wild-type 4R0N form of human tau under the control of the mouse Pgk1 promoter (AAV-tau)

  • Concomitant with the accumulation of human tau, immunohistology revealed in the ipsilateral hippocampus the presence of misfolded tau, tau phosphorylated at Ser202/Thr205 residues (AT8 antibody) as well as tau phosphorylated at Ser396/Ser404 residues (PHF1 antibody) (Additional file 1: Fig. S1c)

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Summary

Introduction

In the absence of any disease-modifying treatment, Alzheimer’s disease (AD) leads to the progressive loss of memory and other cognitive functions. As overexpressing human wild-type (WT) tau in the mouse species does not necessarily trigger conversion to pathological tau species [14], most studies have addressed this question by overexpressing tau carrying pro-aggregant mutations typically associated with frontotemporal dementia [5, 20, 24, 42, 51, 54, 60]. Neuritic plaques facilitate the formation of NFTs following brain inoculation with tau seeds derived from human AD brain [23]. These studies highlight the importance of the interaction between Aβ and WT tau at the level of the neuritic plaques in the development of tau pathology

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