Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation

J Biol Chem. 2019 Aug 23;294(34):12754-12765. doi: 10.1074/jbc.RA119.009487. Epub 2019 Jul 4.

Abstract

In cortical regions of brains from individuals with preclinical or clinical Alzheimer's disease (AD), extracellular β-amyloid (Aβ) deposition precedes the aggregation of pathological intracellular tau (the product of the gene microtubule-associated protein tau (MAPT)). To our knowledge, current mouse models of tauopathy reconstitute tau pathology by overexpressing mutant human tau protein. Here, through a homologous recombination approach that replaced the entire murine Mapt gene with the human ortholog, we developed knock-in mice with humanized Mapt to create an in vivo platform for studying human tauopathy. Of note, the humanized Mapt expressed all six tau isoforms present in humans. We next cross-bred the MAPT knock-in mice with single amyloid precursor protein (App) knock-in mice to investigate the Aβ-tau axis in AD etiology. The double-knock-in mice exhibited higher tau phosphorylation than did single MAPT knock-in mice but initially lacked apparent tauopathy and neurodegeneration, as observed in the single App knock-in mice. We further observed that tau humanization significantly accelerates cell-to-cell propagation of AD brain-derived pathological tau both in the absence and presence of Aβ-amyloidosis. In the presence of Aβ-amyloidosis, tau accumulation was intensified and closely associated with dystrophic neurites, consistently showing that Aβ-amyloidosis affects tau pathology. Our results also indicated that the pathological human tau interacts better with human tau than with murine tau, suggesting species-specific differences between these orthologous pathogenic proteins. We propose that the MAPT knock-in mice will make it feasible to investigate the behaviors and characteristics of human tau in an animal model.

Keywords: Alzheimer disease; amyloid precursor protein (APP); amyloid-beta (AB); dystrophic neurite; humanized mouse model; knock-in; neurodegeneration; plaque deposit; tau propagation; tau protein (tau); tauopathy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • tau Proteins / genetics
  • tau Proteins / metabolism*

Substances

  • MAPT protein, human
  • Mapt protein, mouse
  • tau Proteins