Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes

Kaja Plucińska, Barry Crouch, David Koss, Lianne Robinson, Michael Siebrecht, Gernot Riedel, Bettina Platt

41 Citations (Scopus)

Abstract

Key neuropathological hallmarks of Alzheimer's disease (AD) are elevated levels of amyloid β-peptide (Aβ) species generated via amyloid precursor protein (APP) endoproteolysis and cleavage by the rate-limiting β-site enzyme 1 (BACE1). Because rodents do not develop amyloid pathologies, we here investigated whether AD-like endophenotypes can be created in mice by expression of human bace1. To avoid pitfalls of existing models, we introduced hbace1 via knock-in under the control of the CaMKII α promoter into the safe HPRT locus. We report amyloidogenic processing of murine APP in the hBACE1 mice (termed PLB4), resulting in the formation of toxic APP metabolites that accumulate intra- and extraneuronally in hippocampus and cortex. Pronounced accumulation of Aβ*56 and Aβ hexamers in the absence of plaque deposition was detected in brain tissue from symptomatic PLB4 mice. Heightened levels of inflammation (gliosis) also appeared in several AD-related brain regions (dentate gyrus, hippocampal area CA1, piriform and parietal cortices) at 6 and 12 months of age. Behaviorally, deficits in habituation to a novel environment and semantic-like memory (social transmission of food preference) were detected from 3 to 4 months of age. Impairments in spatial learning strategies in long-term reference (water maze) and working memory (Y-maze) tasks presented at 6 months, and were distinct from reductions in locomotor activity and anxiety. Overall, our data indicate for the first time that targeted, subtle forebrain-specific expression through single gene knock-in of hBACE1 is sufficient to generate AD-relevant cognitive impairments amid corresponding histopathologies, confirming human BACE as the key parameter in amyloid pathogenesis.

Original languageEnglish
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience
Volume34
Issue number32
Pages (from-to)10710-28
Number of pages19
ISSN0270-6474
DOIs
Publication statusPublished - 6 Aug 2014
Externally publishedYes

Keywords

  • Alzheimer Disease/genetics
  • Amyloid Precursor Protein Secretases/genetics
  • Amyloid beta-Peptides/metabolism
  • Amyloid beta-Protein Precursor/metabolism
  • Animals
  • Aspartic Acid Endopeptidases/genetics
  • Circadian Rhythm/genetics
  • Dark Adaptation/genetics
  • Disease Models, Animal
  • Food Preferences/physiology
  • Gait Disorders, Neurologic/etiology
  • Genotype
  • Humans
  • Maze Learning/physiology
  • Memory Disorders/etiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Activity/physiology
  • Phenotype
  • Spatial Behavior/physiology

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