Reduced neuronal BRCA1 associated with decreased DNA repair in Alzheimer’s disease [PreClinical]

1. In a pre-clinical study of post-mortem brains of Alzheimer’s disease (AD) patients, there was an isolated depletion of neuronal Breast Cancer Type 1 Susceptibility Protein (BRCA1), a DNA repair protein, compared to controls.

2. BRCA1-knock out mice models demonstrated memory and spatial learning deficits as well as decreased long-term synaptic plasticity.

Evidence Rating Level: 3 (Average)

Study Rundown: BRCA1 is a tumor suppressor protein commonly associated with breast and ovarian cancer and plays a vital role in the repair of DNA damage. However, it is not clear how BRCA1 may be involved in the development of chronic diseases associated with DNA damage, such as AD. The purpose of this study was to investigate the role of BRCA1 in AD pathogenesis.

The study analyzed BRCA1 levels and DNA double-strand breaks (DSB) in post-mortem brains of patients with AD as well as in amyloid precursor protein (hAPP) transgenic mice. At the conclusion of the trial, there was an isolated reduction of BRCA1 in the post-mortem brains of AD patients compared to controls. Furthermore, increased amyloid burden was associated with significant reduction in BRCA1 in mice models. Additionally, in BRCA1 knockout mice, there was a significant impairment in both memory and spatial learning. Moreover, long-term synaptic plasticity was affected with BRCA1 reduction, which interfered with hippocampus-associated spatial learning and memory. These findings were surprising because BRCA1 was not known to play a physiological role in non-dividing cells, and the mechanistic pathway by which BRCA1 functions in post-mitotic cells is yet to be understood. The results of this paper open the door to other questions, such as if BRCA1 mutations associated with increased risk for certain cancers also change the BRCA1 function in the brain; or if AD patients could benefit from therapeutically enhancing DNA repair.

Click to read the study in Nature

Relevant Reading: Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β

In-Depth [animal study]: This study compared the levels of BRCA1 depletion in brains of Human Amyloid Precursor (hAPP) mice and wild type (WT) mice. The average age of the mice was between 4-8 months. Overall, there was a 70% decrease in BRCA1 levels within the dentate gyrus (DG) of the hAPP group compared to WT. Within the DG, WT and hAPP-J20 mice had normal levels of BRCA, indicating that the BRCA depletion was post-transcriptional. Additionally, the accumulation of amyloid-beta oligomers increased levels of the DSB marker (gamma) H2A.X by 70% and decreased BRCA1 levels by 50% in primary neuronal cultures. Furthermore, neuronal BRCA1 levels in the inferior parietal cortex were analyzed in post-mortem brains of Alzheimer’s patients. Patients with Alzheimer’s had 50-70% lower BRCA1 levels than the control. Functional learning was assessed via Morris water maze and place recognition paradigm. Overall, there was no significant difference in the learning curve of WT and hAPP mice (p = 0.74). However, when both groups received BRCA1 knockdown mutations, there was significant learning and memory deficits in the hAPP group compared to WT.

Image: PD

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