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Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes.
J Neurosci 2014; 34(32):10710-28JN

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.

Authors+Show Affiliations

School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom b.platt@abdn.ac.uk g.riedel@abdn.ac.uk.School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom b.platt@abdn.ac.uk g.riedel@abdn.ac.uk.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25100603

Citation

Plucińska, Kaja, et al. "Knock-in of Human BACE1 Cleaves Murine APP and Reiterates Alzheimer-like Phenotypes." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 34, no. 32, 2014, pp. 10710-28.
Plucińska K, Crouch B, Koss D, et al. Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes. J Neurosci. 2014;34(32):10710-28.
Plucińska, K., Crouch, B., Koss, D., Robinson, L., Siebrecht, M., Riedel, G., & Platt, B. (2014). Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 34(32), pp. 10710-28. doi:10.1523/JNEUROSCI.0433-14.2014.
Plucińska K, et al. Knock-in of Human BACE1 Cleaves Murine APP and Reiterates Alzheimer-like Phenotypes. J Neurosci. 2014 Aug 6;34(32):10710-28. PubMed PMID: 25100603.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes. AU - Plucińska,Kaja, AU - Crouch,Barry, AU - Koss,David, AU - Robinson,Lianne, AU - Siebrecht,Michael, AU - Riedel,Gernot, AU - Platt,Bettina, PY - 2014/8/8/entrez PY - 2014/8/8/pubmed PY - 2014/10/4/medline KW - amyloid KW - circadian KW - cognition KW - inflammation KW - memory KW - strategy SP - 10710 EP - 28 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 34 IS - 32 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/25100603/Knock_in_of_human_BACE1_cleaves_murine_APP_and_reiterates_Alzheimer_like_phenotypes_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=25100603 DB - PRIME DP - Unbound Medicine ER -