title: AAV2/1 CD74 Gene Transfer Reduces β-amyloidosis and Improves Learning and Memory in a Mouse Model of Alzheimer's Disease.
abstract: Modulation of the amyloid-β (Aβ) trafficking pathway heralds a new therapeutic frontier for Alzheimer's disease (AD). As CD74 binds to the amyloid-β precursor protein (APP) and can suppresses Aβ processing, we investigated whether recombinant adeno-associated virus (AAV) delivery of CD74 could reduce Aβ production and affect disease outcomes. This idea was tested in a mouse AD model. Cotransduction of AAV-tetracycline-controlled transactivator (tTA) and AAV-tet-response element (TRE)-CD74 resulted in CD74 expression, reduced Aβ production in mouse neurons containing the human APP with familial AD-linked mutations. Stereotaxic injection of AAV-TRE-GFP or CD74 into the hippocampi of an AD mouse, defined as a TgCRND8 × calmodulin-dependent protein kinase II derived promoter-tTA double-transgenic, reduced Aβ loads and pyramidal neuronal Aβ accumulation in the hippocampus. Immunofluorescent studies showed that APP colocalization with Lamp1 was increased in CD74-expressing neurons. Moreover, Morris water maze tasks demonstrated that mice treated with AAV-TRE-CD74 showed improved learning and memory compared to AAV-TRE-GFP control animals. These results support the idea that CD74-induced alteration of Aβ processing could improve AD-associated memory deficits as shown in mouse models of human disease.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA. Electronic address: tkiyota@unmc.edu.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kiyota
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Morrison
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Bosch
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weir
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Yaman
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Dong
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000523:psychology / Q000628:therapy*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000502:physiology; D000686:Amyloidosis / Q000378:metabolism; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics*; D002478:Cells, Cultured; D000229:Dependovirus; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000627:therapeutic use; D006624:Hippocampus / Q000378:metabolism / Q000601:surgery; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D008845:Microinjections / Q000379:methods; D009474:Neurons / Q000378:metabolism*; D013238:Stereotaxic Techniques; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D016564:Amyloid beta-Protein Precursor; D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; D051907:Lysosomal Membrane Proteins; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C045084:invariant chain