Overactive BRCA1 Affects Presenilin 1 in Induced Pluripotent Stem Cell-Derived Neurons in Alzheimer’s Disease

Abstract

The BRCA1 protein, one of the major players responsible for DNA damage response has recently been linked to Alzheimer's disease (AD). Using primary fibroblasts and neurons reprogrammed from induced pluripotent stem cells (iPSC) derived from familial AD (FAD) patients, we studied the role of the BRCA1 protein underlying molecular neurodegeneration. By whole-transcriptome approach, we have found wide range of disturbances in cell cycle and DNA damage response in FAD fibroblasts. This was manifested by significantly increased content of BRCA1 phosphorylated on Ser1524 and abnormal ubiquitination and subcellular distribution of presenilin 1 (PS1). Accordingly, the iPSC-derived FAD neurons showed increased content of BRCA1(Ser1524) colocalized with degraded PS1, accompanied by an enhanced immunostaining pattern of amyloid-β. Finally, overactivation of BRCA1 was followed by an increased content of Cdc25C phosphorylated on Ser216, likely triggering cell cycle re-entry in FAD neurons. This study suggests that overactivated BRCA1 could both influence PS1 turnover leading to amyloid-β pathology and promote cell cycle re-entry-driven cell death of postmitotic neurons in AD.

Contributions of DNA Damage to Alzheimer’s Disease

“…In this respect, transgenic expression of hAPP in mice leads to decrease in BRCA1 expression; knockdown of BRCA1 in these mice increases neuronal DSBs and apoptosis with concurrent impairment of learning and memory [89]. On the other hand, exploratory activities induced by change in environment upregulate BRCA1 in the dentate gyrus of mouse hippocampus [89]. These results are well in accordance with the concept that physiological neuronal activities increase transcription of early response genes through processes promoted by DSBs [65].…”

“…Reductions in BRCA1's ability in managing DSB repair are suggested in AD brains. Decreases in BRCA1 expression were detected in the hippocampal neurons of not only AD but also MCI brains [89], indicating a causative role of BRCA1 in AD. In this respect, transgenic expression of hAPP in mice leads to decrease in BRCA1 expression; knockdown of BRCA1 in these mice increases neuronal DSBs and apoptosis with concurrent impairment of learning and memory [89].…”

“…Decreases in BRCA1 expression were detected in the hippocampal neurons of not only AD but also MCI brains [89], indicating a causative role of BRCA1 in AD. In this respect, transgenic expression of hAPP in mice leads to decrease in BRCA1 expression; knockdown of BRCA1 in these mice increases neuronal DSBs and apoptosis with concurrent impairment of learning and memory [89]. On the other hand, exploratory activities induced by change in environment upregulate BRCA1 in the dentate gyrus of mouse hippocampus [89].…”

Cancer and dementia: Two sides of the same coin?

“…Moreover, the BRCA1 protein, an important tumour suppressor protein, has recently been linked to AD. Overactivation of BRCA1 can indirectly result in Aβ pathology and can promote neuronal cell death . Furthermore, plasma levels of Aβ‐40 and Aβ‐42 are increased in patients with different cancer types …”

“…Overactivation of BRCA1 can indirectly result in Aβ pathology and can promote neuronal cell death. 80 Furthermore, plasma levels of Aβ-40 and Aβ-42 are increased in patients with different cancer types. 81 DNA damage caused by oxidative stress and deficient DNA repair mechanisms are also important in the pathogenesis of cancer and dementia.…”