title: Amyloid-β precursor protein facilitates the regulator of calcineurin 1-mediated apoptosis by downregulating proteasome subunit α type-5 and proteasome subunit β type-7.
abstract: Individuals with Down syndrome (DS), caused by trisomy of chromosome 21, inevitably develop characteristic Alzheimer's disease (AD) neuropathology, including neuritic plaques, neurofibrillary tangles, and neuronal loss. Amyloid-β protein, the major component of neuritic plaques, is the proteolytic product of amyloid-β precursor protein (APP). APP and the regulator of calcineurin 1 (RCAN1) genes on chromosome 21 play a pivotal role in promoting plaque formation and neuronal apoptosis. However, the mechanism underlying AD pathogenesis in DS is not well defined. In this study, we demonstrated that APP significantly increased RCAN1 level in both cells and transgenic mice. Overexpression of APP significantly reduced the expression of 2 proteasome subunits, proteasome subunit α type-5 and proteasome subunit β type-7, leading to the inhibition of proteasomal degradation of RCAN1. Furthermore, knockdown of RCAN1 expression attenuated APP-induced neuronal apoptosis. Taken together, the results clearly showed that APP has a previously unknown function in regulating RCAN1-mediated neuronal apoptosis through the proteasome pathway. Our study demonstrates a novel mechanism by which overexpression of APP and RCAN1 causes neurodegeneration and AD pathogenesis in DS, and it provides new insights into the potential of targeting APP-induced proteasomal impairment and RCAN1 accumulation for AD and DS treatment.
authors.affiliation: Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders and Ministry of Education Key Lab of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yili
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Shuting
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yawen
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Medical Genetics of China, Central South University, Changsha, Hunan, China.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders and Ministry of Education Key Lab of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders and Ministry of Education Key Lab of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China. Electronic address: tyli@vip.sina.com.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Li
authors.affiliation: Chongqing City Key Lab of Translational Medical Research in Cognitive Development and Learning and Memory Disorders and Ministry of Education Key Lab of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China; Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: weihong@mail.ubc.ca.
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; C531344:PSMB7 protein, human; D046988:Proteasome Endopeptidase Complex
keywords: APP; Alzheimer's disease; Apoptosis; Down syndrome; Proteasome; RCAN1