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Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders

Gregory Hook, Thomas Reinheckel, Junjun Ni, Zhou Wu, Mark Kindy, Christoph Peters and Vivian Hook
Eric Barker, ASSOCIATE EDITOR
Pharmacological Reviews July 2022, 74 (3) 600-629; DOI: https://doi.org/10.1124/pharmrev.121.000527
Gregory Hook
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
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Thomas Reinheckel
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
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Junjun Ni
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
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Zhou Wu
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
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Mark Kindy
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
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Christoph Peters
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
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Vivian Hook
American Life Science Pharmaceuticals, La Jolla, California (G.H.); Institute of Molecular Medicine and Cell Research, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany (T.R.); German Cancer Consortium (DKTK) Partner Site Freiburg, Freiburg, Germany (T.R.); German Cancer Research Center (DKFZ), Heidelberg, Germany (T.R); Center for Biological Signaling Studies BIOSS, Albert Ludwigs University, Freiburg, Germany (T.R.); Key Laboratory of Molecular Medicine and Biotherapy, Department of Biology, School of Life Science, Beijing Institute of Technology, Beijing, China (J.N.); Department of Aging Science and Pharmacology, OBT Research Center, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (Z.W); Taneja College of Pharmacy, Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida (M.K.); James A Haley VAMC, Research Service, Tampa, Florida (M.K.); Institute of Molecular Medicine and Cell Research, Faculty of Biology, Albert Ludwigs University, Freiburg, Germany (C.P.); Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, La Jolla, CA (V.H.); and Department of Neuroscience and Department of Pharmacology, School of Medicine, University of California, La Jolla, CA (V.H.)
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Eric Barker
Roles: ASSOCIATE EDITOR
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  • Fig. 1
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    Fig. 1

    Maturation of CTSB: zymogen conversion to active CTSB. Mature, active CTSB is generated from its inactive zymogen that is converted to the active CTSB enzyme. Preprocathepsin B is generated from its mRNA and its N-terminal signal sequence (SP) is removed by signal peptidase to result in procathepsin B. Procathepsin B undergoes autoproteolysis to remove the propeptide (Pro) to generate the mature CTSB. CTSB may also undergo additional processing into light and heavy chains linked by disulfide bonds. Cys108 (*) represents the active cysteine residue. These sequences of human CTSB were obtained from National Center for Biotechnology Information (NCBI) and UniProt databases.

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    Fig. 2

    CTSB expression in mouse brain regions. (A) Nissl stain of mouse brain. A coronal section of adult mouse brain was subject to Nissl staining (from the Allen Brain Institute (http://www.brain-map.org/). (B) CTSB mRNA expression in mouse brain. In situ hybridization of mouse brain sections was conducted with antisense mRNA to cathepsin B. The relative levels of CTSB mRNA expression are shown at high levels by shades of yellow to red (yellow, highest express); lower relative expression levels are shown in green to blue (blue, lowest level of expression). CTSB displays high expression of the hippocampus and cortex regions (adapted from Hook et al., 2015, DOI: 10.3389/fneur.2015.00178 indicating Frontiers as the original publisher).

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    Fig. 3

    Cathepsin B lysosomal leakage leads to cell death and neuroinflammation in behavioral deficits and neurodegeneration of neurologic disorders. CTSB is normally located within lysosomes. In numerous brain trauma and neurodegenerative disease conditions, lysosomal membrane permeabilization (LMP) results in translocation of CTSB to the cytosol. It is hypothesized that pathogenic cytosolic CTSB activates pathways for cell death and inflammation that result in behavioral deficits and neurodegeneration pathology. CTSB in the cytosol is involved in proteolysis to generate proapoptotic tBid and degrades antiapoptotic Bcl-xL to mediate cell death (Repnik and Turk, 2010; de Castro et al., 2016). Cytosolic CTSB activates production of IL-1β and IL-18 pro-inflammatory factors (Hentze et al., 2003; Bai et al., 2018; Campden and Zhang, 2019) that are released through the gasdermin D pore (GSDMD) (Tsuchiya et al., 2021). Cell death and inflammation result in neurodegeneration and behavioral deficits of numerous neurologic disease conditions.

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    Fig. 4

    APP-695 and APP-751/770 expression and processing in normal and transgenic mouse models of Alzheimer’s disease. (A) Mouse APP-695 (mAPP-695) isoform: (i) normal neuronal expression of mAPP-695 produces mouse Aβ (mAβ) and (ii) transgenic neuronal expression of human APP-695 (hAPP-695), driven by the PDGF promoter, produces human Aβ (hAβ). Panel (i) shows that in normal mouse brain, APP-695 is exclusively expressed in neurons for the production of amyloidogenic Aβ peptides, reported by several studies (Sandbrink et al., 1993; Rohan de Silva et al., 1997). APP-695 is the most abundant APP isoform expressed in the normal brain (Tanaka et al., 1989; Kang and Müller-Hill, 1990; Jacobsen et al., 1991; Rockenstein et al., 1995; Nalivaeva and Turner, 2013). Panel (ii) shows that in transgenic mice expressing hAPP-695 driven by the PDGF promoter, hAPP-695 is present in neurons and produces Aβ (Hook et al., 2009; Kindy et al., 2012; Hook et al., 2014b), which models the normal (nontransgenic) neuronal expression of hAPP-695 and production of Aβ. (B) Mouse APP-751/770 (mAPP-751/770) isoforms: (i) normal glia expression of mAPP-751/770) produces sAPPα and (ii) transgenic neuronal expression of hAPP-751/770, driven by the PDGF promoter, produces hAβ. Panel (i) shows that in normal mouse brain, APP-751/770 is expressed in glia cells (Sandbrink et al., 1993) and produces the nonamyloidogenic sAPPα fragment (Kametani et al., 1993; Nalivaeva and Turner, 2013). APP-751/770 is a minor APP isoform in the brain (Tanaka et al., 1989; Kang and Müller-Hill, 1990; Jacobsen et al., 1991; Rockenstein et al., 1995; Nalivaeva and Turner, 2013). Panel (ii) shows that in transgenic mice expressing hAPP-751/770 driven by the PDGF promoter, with deletions of segments within introns 6 and 7 and an insertion (4 bp) in intron 7 (Games et al., 1995; Rockenstein et al., 1995; Mucke et al., 2000; Mueller-Steiner et al., 2006; Wang et al., 2012), hAPP-751/770 is present in neurons and produces Aβ, which differs from the normal (nontransgenic) glia expression of hAPP-751/770 and production of sAPPα (Kametani et al., 1993; Sandbrink et al., 1993; Nalivaeva and Turner, 2013).

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    Fig. 5

    The consilience of CTSB KO data in neurologic disorders modeled in mice demonstrate CTSB-dependent behavioral deficits and pathology. Evidence for elevation of CTSB in models of brain disorders and amelioration of behavioral deficits and neuropathology by CTSB gene knockout in these models is summarized in this figure. (A) Elevation of CTSB expression results in several behavioral deficits and pathology in several neurologic disorders modeled in mice. Increased levels of CTSB in the brain occurs in numerous neurologic disorders modeled in mice (Table 2). The elevated CTSB in the animal models of brain disorders parallels the increased CTSB found in numerous patients with clinical neurologic disease (Table 1). (B) CTSB gene KO results in substantial improvements in behavioral deficits and pathology of several neurologic disorders modeled in mice. The consilience of results of CTSB gene KO studies in numerous animal models of neurologic disease demonstrate that the absence of CTSB results in substantial improvements in behavioral deficits and pathology (Tables 3 and 4).

Tables

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    TABLE 1

    Elevation of cathepsin B in patients with neurologic disorders

    Clinical ConditionBiofluid or TissueCTSB RegulationFeaturesReference
    ADBrain cortex↑CTSB protein increased by 18-foldBatkulwar et al., 2018
    ADBrain↑High CTSB protein and proteolytic activity abnormally localized at amyloid plaques in brainCataldo and Nixon, 1990
    ADSerum↑Increased CTSB correlates with cognitive deficitsSun et al., 2015
    ADCSF↑Increased CTSB proteinSundelof et al., 2010; Armstrong et al., 2014
    ADCSF↑Increased CTSB protein in AD analyzed by proteomicsZhang et al., 2005
    ADPlasma↑Elevated CTSB protein in mild and severe AD by 50%–80% above controlsMorena et al., 2017
    Periodontitis linked to ADSerum↑Increased CTSB levels by 43%Rong et al., 2020
    HIVBrain and plasma monocytes↑Elevated CTSBRodriguez-Franco et al., 2012; Cantres-Rosario et al., 2013
    ALSSpinal cord↑Increased CTSB expression and proteinKikuchi et al., 2003; Dangond et al., 2004; Offen et al., 2009; Saris et al., 2013
    Severe traumaPlasma↑CTSB activity was elevated 5- to 6-fold in severe trauma leading to organ failureAssfalg-Machleidt et al., 1990; Jochum et al., 1993
    Traumatic brain injuryCSF↑Elevated CTSB protein by twofoldBoutte et al., 2020
    Multiple traumaPlasma↑Elevated CTSB associated with trauma and sepsisJochum et al., 1993
    Vascular pathologyBrain vascular endothelium↑Elevated CTSB levelsAoki et al., 2008
    Guillain-Barre syndromeCSF↑Elevated CTSB activityNagai et al., 2000
    AgingCSF↑Increased CTSB protein correlated positively with ageNilsson et al., 2013
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    TABLE 2

    Elevation of Cathepsin B in Animal Models of Neurologic Disorders

    Animal ModelSpecies, AgeCTSB RegulationCTSB mRNA, Protein, or ActivityTissueReferences
    Alzheimer’s disease, 5XFAD modelMouse, 12 months↑Elevated gene expressionBrainBouter et al., 2014
    Alzheimer’s disease, APPSwe/PS1Mouse, 12 months↑Increased proteinBrainSun et al., 2015
    Periodontitis, Alzheimer’s diseaseMouse, 12 months↑Increased proteinHippocampus brain regionWu et al., 2017
    TBI traumaMouse, 3–5 months, and rat, 2–3 months↑Elevated mRNA, protein and proteolytic activityBrainNatale et al., 2003; Zhang et al., 2006; Luo et al., 2010; Sun et al., 2013; Hook et al., 2014a; Boutte et al., 2020
    Trauma spinal cord contusionRat, 2–3 months↑Increased mRNA, protein, and activityBrainEllis et al., 2004, 2005
    Trauma surgeryMouse, ∼3 months↑Elevated activity in extracellular matrixIntestineVreemann et al., 2009
    Subarachnoid hemorrhageRat, ∼3–4 months↑Increased proteinBrainYu et al., 2014; Wang et al., 2015
    Brain aneurysmRat, 2 months at time of injury, and 5 months for analysis↑Elevated mRNA and activityCerebral aneurysm wallsAoki et al., 2008
    ALS (amyotrophic lateral sclerosis)Mouse, 2–4 months↑Increased mRNASpinal cord motoneuronsFerraiuolo et al., 2007; Offen et al., 2009
    Excitatory epilepsyRat, ∼1 month↑Increased proteinBrain and spinal cordNi et al., 2013
    Excitotoxicity, Huntington’s diseaseRat, 2–3 months↑Elevated proteinBrainWang et al., 2006
    Ischemia, acuteRat, 2–3 months↑Elevated protein and activityBrainTsubokawa et al., 2006
    IschemiaMonkey, adult, and rat, 2–3 months↑Increased protein and activityBrainSeyfried et al., 1997; Yamashima et al., 1998; Tsuchiya et al., 1999; Tsubokawa et al., 2006
    Hypoxia/ischemia, neonatalMouse, neonatal↑Increased mRNA and enzyme proteinMicroglia hippocampusNi et al., 2015
    Meningitis brain infectionMousea↑Increased proteolytic activityHuman THP-1 cellsHoegen et al., 2011
    Sepsis infectionRat, 2 months or 1 month↑Increased proteolytic activitySkeletal muscleRuff and Secrist, 1984; Hummel et al., 1988
    Inflammation, agingMouse, 12 months, and 2, 10, 20 months↑Increased mRNA and proteinBrainWu et al., 2017; Ni et al., 2019
    Inflammatory painMouse, ∼1 month↑Elevated proteinSpinal cordSun et al., 2012
    • aAge not indicated.

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    TABLE 3

    Cathepsin B Knockout Improves Behavioral Deficits in Animal Models of Neurologic Disorders

    Neurologic Disease Mouse Model, Age, SexCathepsin B Knockout in the Neurologic Disease Model Improves OutcomesReferences
    BehaviorsCell PathologyBiomarkers
    Traumatic brain injury: controlled cortical impact mouse model, 15–28 weeks old, male↓Neuromotor deficits↓Brain tissue loss, ↓cell death in hippocampus↓Proapoptotic BaxHook et al., 2014a
    Hypoxia-ischemia: neonatal HI mouse model, neonatal, sex not specifiednd↓Cell death in hippocampus, ↓neuroinflammation↓NF-κB to reduce inflammatory cytokinesNi et al., 2015
    Epilepsy: EPM1, cystatin B KO mouse model, 2, 4, and 8 months old, sex not specifiedNo effect on seizures↓Cell death in neuronal granule cellsndHouseweart et al., 2003
    Multiple sclerosis: EAE mouse model, 8–10 weeks old, female↑Clinical score, ↑ time of disease onset↓Infiltrating immunologic cells, ↓antigen presentationndAllan and Yates, 2015
    Inflammatory pain: CFA model, 5 weeks old, male↓Allodynia behavioral test for pain↓Microglia cell size morphology, ↓decreased microglia extensionsBlockade of CFA-induced increase in IL-1β, IL-18, and COX-2Sun et al., 2012
    Tolerance to opioid: chronic morphine antinociceptive tolerance, 10 weeks old, malePrevents opiate tolerance, ↓pain assessed by thermal hot plate test↓Elevation in excitatory postsynaptic potential↓Glutamate release from spinal neuronsHayashi et al., 2014
    • nd, not determined.

    • View popup
    TABLE 4

    Cathepsin B Gene Knockout Improves Memory Deficits in AD and Aging Models

    Animal ModelhAPP IsotypeCTSB Knockout Improves Memory Deficits and Outcomes in hAPP AD ModelsReferences
    Isotype, Cell Typeβ-Secretase Siteγ-Secretase SiteMemory DeficitsCellular and Biomarker FeaturesPathology
    AgingMouse APP isoforms of 695 in neurons and isoforms 751 and 770 in gliaWTWT↓Memory deficits↓Activated macrophages, ↓inflammatory cytokines, ↓oxidative stress, ↑long-term potentiationndTerada et al., 2010; Ni et al., 2019
    Periodontitis ADMouse APP isoforms of 695 in neurons and 751 and 770 in gliaWTWT↓Memory deficits↓Activated macrophages
    ↓Aβ (1-42), ↓inflammatory cytokines
    ndWu et al., 2017
    ADhAPP-WT-695, neuronal expression (PDGF promoter)WTWTn/a↓Aβ (1–42) by ∼70%
    ↓β (1–40) by ∼70%
    ↓CTFβ by 40%, ↑sAPPα by 60%, ↓WT β-secretase activity
    n/aHook et al., 2009
    ADhAPP-WT-Lon-695, neuronal expression (PDGF promoter)WTLon, V717I↓Memory deficits↓Aβ(1–40) by 85%
    ↓Aβ(1–42) by 87%
    ↓pGluAβ(3–40) by 65%
    ↓pGluAβ(3–42) by 92%
    ↓CTFβ by 60%
    ↑sAβPPα by 60%
    ↓WT β-secretase activity
    ↓Aβ plaque by 85%, ↓pGluAβ plaque by 46%Kindy et al., 2012; Hook et al., 2014b
    ADhAPP-Swe-Lon-695, neuronal expression (PDGF promoter)Swe, K670N/M671LLon, V717INo effect on memory deficitsNo effects on Aβ(1–42), CTFβ, or APPαNo effect on amyloid plaqueKindy et al., 2012
    ADhAPP-Swe-Ind-695, neuronal expression (PDGF promoter)Swe K670N/M671LInd, V717Fn/aNo effects on Aβ, CTFβ, or sAPPαn/aHook et al., 2009
    ADhAPP-Swe-Ind-751/770, neuronal expression (PDGF promoter), J20 line, introns modified, PDAPP)SweIndndNo change in fIAPP, β-CTF, α-sAPP, or α-CTF
    ↑Aβ(1–42)/Aβ(1–x) ratio by ∼25%
    Elevated plaque loadMueller-Steiner et al., 2006
    ADhAPP-751/770, neuronal expression (PDGF promoter, I63 line, introns modified, PDAPP)WTWTndNo change in hippocampal Aβ42, ↑cortical Aβ42 by 12%ndWang et al., 2012
    • nd, not determined; n/a, not applicable.

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Review ArticleReview Article

Cathepsin B in Neurologic Diseases

Gregory Hook, Thomas Reinheckel, Junjun Ni, Zhou Wu, Mark Kindy, Christoph Peters and Vivian Hook
Pharmacological Reviews July 1, 2022, 74 (3) 600-629; DOI: https://doi.org/10.1124/pharmrev.121.000527

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Review ArticleReview Article

Cathepsin B in Neurologic Diseases

Gregory Hook, Thomas Reinheckel, Junjun Ni, Zhou Wu, Mark Kindy, Christoph Peters and Vivian Hook
Pharmacological Reviews July 1, 2022, 74 (3) 600-629; DOI: https://doi.org/10.1124/pharmrev.121.000527
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  • Article
    • Abstract
    • I. Introduction
    • II. Cathepsin B is Elevated in Human Neurologic Disorders
    • III. Cathepsin B Genetic Mutations Increase Cathepsin B and Cause Human Diseases
    • IV. Cathepsin B Is Elevated in Animal Models of Neurologic Diseases
    • V. Cathepsin B Neurobiology
    • VI. Gene Knockout Mice for Target Validation and Drug Discovery
    • VII. Cathepsin B Knockout Mice Are Generally Indistinguishable from Wild-Type Healthy Animals
    • VIII. Cathepsin B Knockout Improves Behavioral Deficits in Neurologic Disease Animal Models
    • IX. Cathepsin B Upregulation Is a Common Response in Neurologic Disorders and Causes Cellular Pathology by Multiple Specific Mechanisms
    • X. Summary and Conclusion: Cathepsin B Knockout Data Validates Cathepsin B as a Drug Target for Development of Cathepsin B Inhibitors as Potentially New Therapeutics for Neurologic Disorders
    • XI. Significance
    • Acknowledgments
    • Authorship Contributions
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