Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model.
In Alzheimer disease, increased beta-secretase (BACE1) activity has been associated with neurodegeneration and accumulation of amyloid precursor protein (APP) products. Thus, inactivation of BACE1 could be important in the treatment of Alzheimer disease. In this study, we found that lowering BACE1 levels using lentiviral vectors expressing siRNAs targeting BACE1 reduced amyloid production and the neurodegenerative and behavioral deficits in APP transgenic mice, a model of Alzheimer disease. Our results suggest that lentiviral vector delivery of BACE1 siRNA can specifically reduce the cleavage of APP and neurodegeneration in vivo and indicate that this approach could have potential therapeutic value for treatment of Alzheimer disease.
Singer
Oded
O
Laboratory of Genetics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
Marr
Robert A
RA
Rockenstein
Edward
E
Crews
Leslie
L
Coufal
Nicole G
NG
Gage
Fred H
FH
Verma
Inder M
IM
Masliah
Eliezer
E
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002460:Cell Line; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005822:Genetic Vectors / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016086:Lentivirus / Q000502:physiology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000627:therapeutic use*; D013037:Spatial Behavior / Q000187:drug effects; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse