Knock-in of Human BACE1 Cleaves Murine APP and Reiterates Alzheimer-like PhenoTypes

Kaja Plucinska, Barry Crouch, David Koss, Lianne Robinson, Gernot Riedel, Bettina Platt (Corresponding Author)

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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
Pages (from-to)10710-10728
Number of pages19
JournalJournal of Neuroscience
Volume34
Issue number32
DOIs
Publication statusPublished - 6 Aug 2014

Fingerprint

Amyloid beta-Protein Precursor
Alzheimer Disease
Amyloid
Phenotype
Gene Knock-In Techniques
Endophenotypes
Hypoxanthine Phosphoribosyltransferase
Food Preferences
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Parietal Lobe
Gliosis
Poisons
Dentate Gyrus
Brain
Locomotion
Prosencephalon
Short-Term Memory
Semantics
Rodentia
Hippocampus

Keywords

  • BACE1
  • amyloid
  • circadian
  • cognition
  • inflammation
  • memory
  • strategy

Cite this

Knock-in of Human BACE1 Cleaves Murine APP and Reiterates Alzheimer-like PhenoTypes. / Plucinska, Kaja; Crouch, Barry; Koss, David; Robinson, Lianne; Riedel, Gernot; Platt, Bettina (Corresponding Author).

In: Journal of Neuroscience, Vol. 34, No. 32, 06.08.2014, p. 10710-10728.

Research output: Contribution to journalArticle

Plucinska, Kaja ; Crouch, Barry ; Koss, David ; Robinson, Lianne ; Riedel, Gernot ; Platt, Bettina. / Knock-in of Human BACE1 Cleaves Murine APP and Reiterates Alzheimer-like PhenoTypes. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 32. pp. 10710-10728.
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AU - Plucinska, Kaja

AU - Crouch, Barry

AU - Koss, David

AU - Robinson, Lianne

AU - Riedel, Gernot

AU - Platt, Bettina

N1 - Footnotes We thank Roemex and the College for Life Science and Medicine at the University of Aberdeen for their generous support. The authors declare no competing financial interests.

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N2 - 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.

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KW - memory

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