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 language | English |
|---|---|
| Journal | The Journal of neuroscience : the official journal of the Society for Neuroscience |
| Volume | 34 |
| Issue number | 32 |
| Pages (from-to) | 10710-28 |
| Number of pages | 19 |
| ISSN | 0270-6474 |
| DOIs | |
| Publication status | Published - 6 Aug 2014 |
| Externally published | Yes |
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
