Neuron Loss and Behavioral Deficits in the TBA42 Mouse Model Expressing N-Truncated Pyroglutamate Amyloid-β3-42

J Alzheimers Dis. 2015;45(2):471-82. doi: 10.3233/JAD-142868.

Abstract

Pyroglutamate-modified amyloid-β (Aβ) at amino acid position three (Aβ(pE3-42)) is gaining considerable attention as a potential key player in the pathogenesis of Alzheimer's disease (AD). Aβ(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability, and cellular toxicity. The aim of the present work was to study the effect of Aβ(pE3-42) expression on neuron loss and associated behavioral deficits using the TBA42 transgenic mouse model. Expression of pyroglutamate Aβ(3-42) triggers hippocampal CA1 neuron loss and behavioral deficits in the TBA42 mouse model. Mice elicited significant neuron death (-35% at the age of 12 months), deficits in the spatial reference memory, working memory, loss of anxiety, and severe motor deficits in an age-dependent manner. These results support a major pathological function of pyroglutamate Aβ in AD.

Keywords: Hippocampus; N-truncated Aβ; motor deficits; spatial reference memory; stereology; transgenic mouse model; working memory.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Alzheimer Disease* / complications
  • Alzheimer Disease* / genetics
  • Alzheimer Disease* / pathology
  • Amyloid beta-Peptides / genetics*
  • Animals
  • CA1 Region, Hippocampal / pathology*
  • Cell Death / genetics
  • Disease Models, Animal
  • Humans
  • Maze Learning / physiology
  • Mental Disorders / etiology*
  • Mice
  • Mice, Transgenic
  • Movement Disorders / etiology
  • Muscle Strength / genetics
  • Neurons / pathology*
  • Peptide Fragments / genetics*
  • Psychomotor Performance / physiology
  • Spatial Learning / physiology

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (3-42), pyroglutamyl(3)-