Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes.
J Neurosci
; 34(32): 10710-28, 2014 Aug 06.
Article
en En
| MEDLINE
| ID: mdl-25100603
ABSTRACT
Key neuropathological hallmarks of Alzheimer's disease (AD) are elevated levels of amyloid ß-peptide (Aß) species generated via amyloid precursor protein (APP) endoproteolysis and cleavage by the rate-limiting ß-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 Aß*56 and Aß 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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Fenotipo
/
Péptidos beta-Amiloides
/
Ácido Aspártico Endopeptidasas
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Precursor de Proteína beta-Amiloide
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Secretasas de la Proteína Precursora del Amiloide
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Enfermedad de Alzheimer
Tipo de estudio:
Etiology_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Neurosci
Año:
2014
Tipo del documento:
Article
País de afiliación:
Reino Unido