title: Cathepsin B Improves ß-Amyloidosis and Learning and Memory in Models of Alzheimer's Disease.
abstract: Amyloid-ß (Aß) precursor protein (APP) metabolism engages neuronal endolysosomal pathways for Aß processing and secretion. In Alzheimer's disease (AD), dysregulation of APP leads to excess Aß and neuronal dysfunction; suggesting that neuronal APP/Aß trafficking can be targeted for therapeutic gain. Cathepsin B (CatB) is a lysosomal cysteine protease that can lower Aß levels. However, whether CatB-modulation of Aß improves learning and memory function deficits in AD is not known. To this end, progenitor neurons were infected with recombinant adenovirus expressing CatB and recovered cell lysates subjected to proteomic analyses. The results demonstrated Lamp1 deregulation and linkages between CatB and the neuronal phagosome network. Hippocampal injections of adeno-associated virus expressing CatB reduced Aß levels, increased Lamp1 and improved learning and memory. The findings were associated with the emergence of c-fos + cells. The results support the idea that CatB can speed Aß metabolism through lysosomal pathways and as such reduce AD-associated memory deficits.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Embury
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Bhagyalaxmi
authors.initials: B
authors.lastname: Dyavarshetty
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Yaman
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Jayme L
authors.initials: JL
authors.lastname: Wiederin
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Ciborowski
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA. hegendel@unmc.edu.|Department of Internal Medicine, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE, 68198-5880, USA. hegendel@unmc.edu.
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kiyota
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000686:Amyloidosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002401:Cathepsin B / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007858:Learning / Q000187:drug effects* / Q000502:physiology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects* / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D002401:Cathepsin B
keywords: Adeno-associated virus; Gene therapy; Lysosomal degrading enzyme; Proteomics; Radial arm water maze