Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer's disease mouse model

J Neurosci. 2015 Mar 25;35(12):4857-68. doi: 10.1523/JNEUROSCI.4989-14.2015.

Abstract

In Alzheimer's disease (AD), the pathological accumulation of tau appears to be a downstream effect of amyloid β protein (Aβ). However, the relationship between these two proteins and memory loss is unclear. In this study, we evaluated the specific removal of pathological tau oligomers in aged Tg2576 mice by passive immunotherapy using tau oligomer-specific monoclonal antibody. Removal of tau oligomers reversed memory deficits and accelerated plaque deposition in the brain. Surprisingly, Aβ*56 levels decreased, suggesting a link between tau and Aβ oligomers in the promotion of cognitive decline. The results suggest that tau oligomerization is not only a consequence of Aβ pathology but also a critical mediator of the toxic effects observed afterward in AD. Overall, these findings support the potential of tau oligomers as a therapeutic target for AD.

Keywords: Alzheimer's disease; Aβ*56; Tau oligomers; Tg2576; immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / metabolism
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Disease Models, Animal
  • Male
  • Memory Disorders / drug therapy
  • Mice
  • Mice, Transgenic
  • Peptide Fragments / immunology
  • Plaque, Amyloid / metabolism
  • tau Proteins / immunology
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Antibodies, Monoclonal
  • Peptide Fragments
  • tau Proteins