title: 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 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.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.
authors.forename: Kaja
authors.initials: K
authors.lastname: Plucińska
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.
authors.forename: Barry
authors.initials: B
authors.lastname: Crouch
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Koss
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.
authors.forename: Lianne
authors.initials: L
authors.lastname: Robinson
authors.affiliation: School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Siebrecht
authors.affiliation: 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.
authors.forename: Gernot
authors.initials: G
authors.lastname: Riedel
authors.affiliation: 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.
authors.forename: Bettina
authors.initials: B
authors.lastname: Platt
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm / Q000235:genetics; D003623:Dark Adaptation / Q000235:genetics; D004195:Disease Models, Animal; D005518:Food Preferences / Q000502:physiology; D020233:Gait Disorders, Neurologic / Q000209:etiology / Q000235:genetics; D005838:Genotype; D006801:Humans; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D010641:Phenotype; D013037:Spatial Behavior / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human
keywords: amyloid; circadian; cognition; inflammation; memory; strategy
references.citation: Neuroimage. 2011 Feb 14;54(4):2603-11
references.pmid: 21093594
references.citation: J Neurosci. 2005 Dec 14;25(50):11693-709
references.pmid: 16354928
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6415-20
references.pmid: 18434550
references.citation: EMBO J. 2012 Jun 22;31(14):3157-68
references.pmid: 22728825
references.citation: Learn Mem. 2004 May-Jun;11(3):337-46
references.pmid: 15169864
references.citation: Mol Cell Neurosci. 2003 Nov;24(3):646-55
references.pmid: 14664815
references.citation: Hum Mol Genet. 2001 Jun 1;10(12):1317-24
references.pmid: 11406613
references.citation: Behav Brain Res. 2010 Mar 17;208(1):169-77
references.pmid: 19931570
references.citation: J Biol Chem. 2004 Dec 10;279(50):52535-42
references.pmid: 15452128
references.citation: Neurobiol Aging. 2008 Jun;29(6):861-73
references.pmid: 17331621
references.citation: Nature. 1999 Dec 2;402(6761):537-40
references.pmid: 10591214
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18367-72
references.pmid: 19837693
references.citation: Mol Neurodegener. 2013 Oct 22;8:34
references.pmid: 24148205
references.citation: Behav Brain Res. 2011 Oct 31;224(2):408-12
references.pmid: 21741995
references.citation: Learn Mem. 2000 Sep-Oct;7(5):333-40
references.pmid: 11040265
references.citation: Br J Pharmacol. 2009 Apr;156(7):1154-66
references.pmid: 19378378
references.citation: J Neural Transm (Vienna). 2004 Mar;111(3):413-25
references.pmid: 14991462
references.citation: Am J Pathol. 2006 Jan;168(1):184-94
references.pmid: 16400022
references.citation: Science. 1999 Oct 22;286(5440):735-41
references.pmid: 10531052
references.citation: Neuropsychologia. 2013 Apr;51(5):930-7
references.pmid: 23369803
references.citation: J Neurosci. 2007 Jan 24;27(4):751-61
references.pmid: 17251414
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2003 May 15;119B(1):44-7
references.pmid: 12707937
references.citation: PLoS One. 2013 Aug 30;8(8):e72457
references.pmid: 24023619
references.citation: Acta Neuropathol. 2013 May;125(5):699-709
references.pmid: 23525537
references.citation: FASEB J. 2004 Jun;18(9):1034-6
references.pmid: 15059975
references.citation: Biochem J. 2012 Jan 1;441(1):285-96
references.pmid: 21880018
references.citation: J Neurosci. 2008 Aug 27;28(35):8677-81
references.pmid: 18753368
references.citation: Nat Neurosci. 2001 Mar;4(3):231-2
references.pmid: 11224535
references.citation: Nat Cell Biol. 2007 Jul;9(7):755-64
references.pmid: 17576410
references.citation: Neuron. 2013 Aug 7;79(3):447-60
references.pmid: 23931995
references.citation: Exp Physiol. 2000 Nov;85(6):627-34
references.pmid: 11187958
references.citation: Behav Brain Res. 2013 Aug 1;250:148-56
references.pmid: 23643691
references.citation: J Neurosci. 2010 Jan 13;30(2):505-14
references.pmid: 20071513
references.citation: J Neurosci Methods. 1985 Aug;14(3):149-67
references.pmid: 2864480
references.citation: PLoS One. 2013 Sep 23;8(9):e75125
references.pmid: 24086453
references.citation: J Proteome Res. 2011 Mar 4;10(3):1416-9
references.pmid: 21186791
references.citation: Curr Genomics. 2007 Dec;8(8):509-30
references.pmid: 19415126
references.citation: Front Physiol. 2012 Feb 17;3:8
references.pmid: 22363289
references.citation: J Neurochem. 2002 Mar;80(5):799-806
references.pmid: 11948243
references.citation: Nat Med. 2003 Jan;9(1):3-4
references.pmid: 12514700
references.citation: J Neurochem. 2010 Feb;112(4):1045-53
references.pmid: 19968762
references.citation: Nature. 2006 Mar 16;440(7082):352-7
references.pmid: 16541076
references.citation: Nat Neurosci. 2001 Mar;4(3):233-4
references.pmid: 11224536
references.citation: Neurobiol Dis. 2007 Apr;26(1):134-45
references.pmid: 17258906
references.citation: Behav Brain Res. 2011 Sep 12;222(1):169-75
references.pmid: 21443906
references.citation: Alzheimers Dement. 2010 Nov;6(6):465-74
references.pmid: 21044776
references.citation: Pharmacol Biochem Behav. 1980 Aug;13(2):167-70
references.pmid: 6106204
references.citation: J Neurosci. 2013 Dec 4;33(49):19276-83
references.pmid: 24305823
references.citation: Neuron. 1997 Oct;19(4):939-45
references.pmid: 9354339
references.citation: Behav Brain Res. 2009 Feb 11;197(2):466-8
references.pmid: 18977397
references.citation: Neurogenetics. 2001 Oct;3(4):203-6
references.pmid: 11714100
references.citation: PLoS One. 2009;4(5):e5464
references.pmid: 19421325
references.citation: PLoS One. 2011;6(11):e27068
references.pmid: 22096518
references.citation: J Alzheimers Dis. 2011;26(1):105-26
references.pmid: 21558645
references.citation: Am J Pathol. 2000 Jan;156(1):15-20
references.pmid: 10623648
references.citation: Brain. 2012 Sep;135(Pt 9):2699-710
references.pmid: 22525157
references.citation: J Biol Chem. 2002 Feb 15;277(7):4687-93
references.pmid: 11741910
references.citation: Cell Mol Life Sci. 2013 Jul;70(14):2603-19
references.pmid: 23535719
references.citation: Cell Calcium. 2013 Feb;53(2):125-38
references.pmid: 23218930
references.citation: J Neurosci. 2012 Aug 15;32(33):11390-5
references.pmid: 22895721
references.citation: J Alzheimers Dis. 2012;28(4):823-37
references.pmid: 22112550
references.citation: Brain. 2013 May;136(Pt 5):1383-98
references.pmid: 23576130
references.citation: Front Aging Neurosci. 2010 Mar 10;2:8
references.pmid: 20552046
references.citation: J Neurochem. 2010 Apr;113(1):248-61
references.pmid: 20089133
references.citation: Arch Neurol. 2002 Sep;59(9):1381-9
references.pmid: 12223024
references.citation: J Biol Chem. 2012 Dec 7;287(50):41774-86
references.pmid: 23060451
references.citation: J Comp Neurol. 1998 Jul 20;397(1):139-47
references.pmid: 9671284
references.citation: PLoS One. 2009 Dec 29;4(12):e8477
references.pmid: 20041192
references.citation: Neuropsychologia. 2008 Jan 31;46(2):497-510
references.pmid: 17936858
references.citation: Biochemistry. 2000 Sep 5;39(35):10831-9
references.pmid: 10978169
references.citation: Science. 2006 Oct 27;314(5799):664-6
references.pmid: 16990514
references.citation: Exp Neurol. 2006 Feb;197(2):330-40
references.pmid: 16309676
references.citation: Neurosci Biobehav Rev. 2012 May;36(5):1357-75
references.pmid: 22373961
references.citation: Curr Protoc Neurosci. 2009 Jul;Chapter 8:Unit 8.24
references.pmid: 19575474
references.citation: Cell Mol Life Sci. 2013 Jul;70(14):2585-601
references.pmid: 23407662