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.
journal_name
Neurobiol Agingjournal_title
Neurobiology of agingauthors
Wu Y,Deng Y,Zhang S,Luo Y,Cai F,Zhang Z,Zhou W,Li T,Song Wdoi
10.1016/j.neurobiolaging.2014.07.029subject
Has Abstractpub_date
2015-01-01 00:00:00pages
169-77issue
1eissn
0197-4580issn
1558-1497pii
S0197-4580(14)00498-9journal_volume
36pub_type
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