期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 36, 期 5, 页码 2609-2618出版社
WILEY
DOI: 10.1111/j.1460-9568.2012.08178.x
关键词
Alzheimer's disease; amyloid precursor protein; PS1 mice; cell cycle; gene expression; lymphocytes; polymerase chain reaction arrays
资金
- Ministry of Science and Innovation [SAF2007-624505, SAF2010-1700, SAF2011-28603]
- CIBERER [11-374/11202]
- Instituto de Salud Carlos III [PI060155]
- Fundacion Investigacion Medica Mutua Madrilena [2006.125, 2008.93]
- CIBERNED
- JAE pre-doctoral program of the CSIC
Cumulative evidence indicates that aberrant re-expression of many cell cycle-related proteins and inappropriate neuronal cell cycle control are critical events in Alzheimers disease (AD) pathogenesis. Evidence of cell cycle activation in post-mitotic neurons has also been observed in murine models of AD, despite the fact that most of these mice do not show massive loss of neuronal bodies. Dysfunction of the cell cycle appears to affect cells other than neurons, as peripheral cells, such as lymphocytes and fibroblasts from patients with AD, show an altered response to mitogenic stimulation. We sought to determine whether cell cycle disturbances are present simultaneously in both brain and peripheral cells from the amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD, in order to validate the use of peripheral cells from patients not only to study cell cycle abnormalities as a pathogenic feature of AD, but also as a means to test novel therapeutic approaches. By using cell cycle pathway-specific RT2Profiler (TM) PCR Arrays, we detected changes in a number of cell cycle-related genes in brain as well as in lymphocytes from APP/PS1 mice. Moreover, we found enhanced 5'-bromo-2'-deoxyuridine incorporation into DNA in lymphocytes from APP/PS1 mice, and increased expression of the cell proliferation marker proliferating cell nuclear antigen (PCNA), and the cyclin-dependent kinase (CDK) inhibitor Cdkn2a, as detected by immunohistochemistry in cortical neurons of the APP/PS1 mice. Taken together, the cell cycle-related changes in brain and blood cells reported here support the mitosis failure hypothesis in AD and validate the use of peripheral cells as surrogate tissue to study the molecular basis of AD pathogenesis.
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