Dine J, Jean-Louis T, Figueiredo-Pereira ME. Relationship between BRCA1 and neuroinflammation mediated by PGJ2: relationship to Alzheimer's disease and cancer-related cognitive impairment. Poster presented at the Neuroscience 2017 Conference; November 14, 2017. Washington, DC.

Alzheimer’s disease (AD) affects approximately 5 million people in the United States and is the leading cause of dementia in older adults. Interestingly, AD shares several genotypic and phenotypic features with cancer-related cognitive impairment (CRCI), which presents in an estimated 75% during and 35% months to years after treatment, most notably in breast and ovarian cancer survivors. Both AD and CRCI are strongly associated with aging, cognitive dysfunction, inflammation, and DNA damage response changes. Decreased expression of BRCA1, an E3 ubiquitin ligase responsible for DNA double-strand break repair and mediating apoptotic signaling, has been identified in the neurons of individuals with mild cognitive impairment and AD. Deleterious BRCA1 variants that result in loss of functional activity are also associated with breast and ovarian cancer development, among other conditions, due to impaired DNA quality control mechanisms. Thus, BRCA1 loss may be a shared feature of AD and CRCI and warrants investigation, particularly in the context of the neurotoxic prostaglandin J2 (PGJ2). PGJ2 is an endogenous product of inflammation and is considered to be one of the most toxic prostaglandins that is produced downstream from cyclooxygenase-2 (COX-2) activation. COX-2 is highly expressed in AD brains and its activity correlates with the severity of AD. Our in vitro studies with human neuroblastoma SY5Y cells overexpressing APP695 (APP695-SY5Y), showed that PGJ2 recapitulates pathological events relevant to AD, including neurotoxicity, caspase-3 activation, tau aggregation, and the accumulation/aggregation of ubiquitinated proteins. We determined the effect of PGJ2 on BRCA1 expression in APP695- SY5Y cells. Upon PGJ2-treatment, the levels of BRCA1 were decreased in a concentrationdependent manner, assessed by western blot analysis. Our findings indicate that BRCA1 expression is attenuated in the presence of PGJ2. This study establishes a potential relationship between BRCA1 and PGJ2 in human neuronal cells for what we believe to be the first time. Further study is needed to investigate PGJ2, as well other the other neuroinflammatory prostaglandins PGD2 and PGE2, and BRCA1 signaling interactions. Such work may lead to the identification of potentially novel therapeutic targets for the treatment of AD and CRCI.

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