Dataset Information

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

ABSTRACT: Key neuropathological hallmarks of Alzheimer's disease (AD) are elevated levels of amyloid ?-peptide (A?) species generated via amyloid precursor protein (APP) endoproteolysis and cleavage by the rate-limiting ?-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 ? 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 A?*56 and A? 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.

SUBMITTER: Plucinska K

PROVIDER: S-EPMC4122804 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Plucińska Kaja K Crouch Barry B Koss David D Robinson Lianne L Siebrecht Michael M Riedel Gernot G Platt Bettina B

The Journal of neuroscience : the official journal of the Society for Neuroscience 20140801 32

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 pr ...[more]

PMID: 25100603

Similar Datasets

Project description:BACKGROUND:Alzheimer's disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-? peptide (A?), which is derived from APP through sequential proteolytic cleavage by BACE1 and ?-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. METHODS:To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized A? sequence. RESULTS:Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble A?, A? oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble A?, A? oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. CONCLUSIONS:hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-A? treatments.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets