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

N1 - Copyright © 2014 the authors 0270-6474/14/3410710-19$15.00/0.

PY - 2014/8/6

Y1 - 2014/8/6

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.

AB - 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.

KW - Alzheimer Disease/genetics

KW - Amyloid Precursor Protein Secretases/genetics

KW - Amyloid beta-Peptides/metabolism

KW - Amyloid beta-Protein Precursor/metabolism

KW - Animals

KW - Aspartic Acid Endopeptidases/genetics

KW - Circadian Rhythm/genetics

KW - Dark Adaptation/genetics

KW - Disease Models, Animal

KW - Food Preferences/physiology

KW - Gait Disorders, Neurologic/etiology

KW - Genotype

KW - Humans

KW - Maze Learning/physiology

KW - Memory Disorders/etiology

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Motor Activity/physiology

KW - Phenotype

KW - Spatial Behavior/physiology

U2 - 10.1523/JNEUROSCI.0433-14.2014

DO - 10.1523/JNEUROSCI.0433-14.2014

M3 - Journal article

C2 - 25100603

VL - 34

SP - 10710

EP - 10728

JO - The Journal of neuroscience : the official journal of the Society for Neuroscience

JF - The Journal of neuroscience : the official journal of the Society for Neuroscience

SN - 0270-6474

IS - 32

ER -