Knock-In of Human BACE1 Cleaves Murine APP and Reiterates Alzheimer-like Phenotypes
| Autor: | Kaja Plucinska, Bettina Platt, David J. Koss, Barry Crouch, Michael Siebrecht, Gernot Riedel, Lianne Robinson |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Genotype
Spatial Behavior Dark Adaptation Mice Transgenic Water maze Hippocampal formation Motor Activity Amyloid beta-Protein Precursor Food Preferences Mice Alzheimer Disease Gene knockin mental disorders medicine Amyloid precursor protein Animals Aspartic Acid Endopeptidases Humans Maze Learning Gait Disorders Neurologic Memory Disorders Amyloid beta-Peptides biology General Neuroscience Dentate gyrus Articles medicine.disease Circadian Rhythm Mice Inbred C57BL Disease Models Animal Phenotype Gliosis biology.protein Alzheimer's disease medicine.symptom Amyloid Precursor Protein Secretases Psychology Amyloid precursor protein secretase Neuroscience |
| Popis: | Key neuropathological hallmarks of Alzheimer9s 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. |
| Databáze: | OpenAIRE |
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