p-Tau immunotherapy reduces soluble and insoluble tau in aged 3xTg-AD mice

Neurosci Lett. 2014 Jul 11;575:96-100. doi: 10.1016/j.neulet.2014.05.047. Epub 2014 Jun 2.

Abstract

Alzheimer's disease (AD) is a proteinopathy characterized by the accumulation of β-amyloid (Aβ) and tau. To date, clinical trials indicate that Aβ immunotherapy does not improve cognition. Consequently, it is critical to modulate other aspects of AD pathology. As such, tau represents an excellent target, as its accumulation better correlates with cognitive impairment. To determine the effectiveness of targeting pathological tau, with Aβ pathology present, we administered a single injection of AT8, or control antibody, into the hippocampus of aged 3xTg-AD mice. Extensive data indicates that phosphorylated Ser(202) and Thr(205) sites of tau (corresponding to the AT8 epitope) represent a pathologically relevant target for AD. We report that immunization with AT8 reduced somatodendritic tau load, p-tau immunoreactivity, and silver stained positive neurons, without affecting Aβ pathology. We also discovered that tau pathology soon reemerges post-injection, possibly due to persistent Aβ pathology. These studies provide evidence that targeting p-tau may represent an effective treatment strategy: potentially in conjunction with Aβ immunotherapy.

Keywords: Alzheimer's disease; Beta-amyloid; Immunotherapy; Neurofibrillary tangles; Phosphorylated tau; Tau.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / immunology
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / therapy*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Antibodies / therapeutic use*
  • Epitopes
  • Immunotherapy
  • Mice, Transgenic
  • Phosphorylation
  • tau Proteins / immunology*
  • tau Proteins / metabolism

Substances

  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Antibodies
  • Epitopes
  • tau Proteins