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. 2007 May 12;4(3):140-5.
doi: 10.7150/ijms.4.140.

BRCA1 may modulate neuronal cell cycle re-entry in Alzheimer disease

Teresa A Evans  1 , Arun K Raina, André Delacourte, Olga Aprelikova, Hyoung-gon Lee, Xiongwei Zhu, George Perry, Mark A Smith
Affiliations

BRCA1 may modulate neuronal cell cycle re-entry in Alzheimer disease

Teresa A Evans et al. Int J Med Sci. .

Abstract

In Alzheimer disease, neuronal degeneration and the presence of neurofibrillary tangles correlate with the severity of cognitive decline. Neurofibrillary tangles contain the antigenic profile of many cell cycle markers, reflecting a re-entry into the cell cycle by affected neurons. However, while such a cell cycle re-entry phenotype is an early and consistent feature of Alzheimer disease, the mechanisms responsible for neuronal cell cycle are unclear. In this regard, given that a dysregulated cell cycle is a characteristic of cancer, we speculated that alterations in oncogenic proteins may play a role in neurodegeneration. To this end, in this study, we examined brain tissue from cases of Alzheimer disease for the presence of BRCA1, a known regulator of cell cycle, and found intense and specific localization of BRCA1 to neurofibrillary tangles, a hallmark lesion of the disease. Analysis of clinically normal aged brain tissue revealed systematically less BRCA1, and surprisingly in many cases with apparent phosphorylated tau-positive neurofibrillary tangles, BRCA1 was absent, yet BRCA1 was present in all cases of Alzheimer disease. These findings not only further define the cell cycle reentry phenotype in Alzheimer disease but also indicate that the neurofibrillary tangles which define Alzheimer disease may have a different genesis from the neurofibrillary tangles of normal aging.

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Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1
Monoclonal antibody to BRCA1 recognizes intracellular NFT in all cases of AD (A), yet in many control cases, no structures are stained (B). On adjacent serial sections, the specific localization of BRCA1 to NFT (C) is completely abolished following adsorption with antigen (D). * marks landmark vessel. Scale bar= 50 μm.
Figure 2
Figure 2
All AD cases and all clinically normal cases showing AT8-positive NFT consistent with normal aging were also analyzed for the presence of BRCA1-positive NFT. All AD cases (100%) at all age ranges exhibited BRCA1 positive NFT. Yet only about half of the control cases with NFT displayed BRCA1 positivity.
Figure 3
Figure 3
The number of NFT stained for BRCA1 and AT8 were counted in the CA1/CA2 regions of hippocampus in well characterized cases of AD (n = 3), MCI (n = 3), and control (n = 4). In AD, an average 28% of AT8-positive NFT contained BRCA1. That number was only 18% for cases of MCI and 9% for the control cases. While all four control cases contained AT8-positive NFT, only two cases displayed BRCA1, a finding similar to that observed with the aged controls examined in Figure 2.
Figure 4
Figure 4
The localization patterns of AT8 and BRCA1 in the different disease states varies greatly. AD cases show high numbers of AT8-positive NFT (B), with many overlapping with BRCA1 localization (A). In cases of MCI, while there are fewer AT8-positive NFT (D), many overlap with BRCA1 (C). Yet in about half of the aged control cases, while there are moderate numbers of AT8-positive NFT (F), BRCA1 is absent (E). * denotes landmark vessels on adjacent serial sections. Arrow mark NFT labeled for both BRCA1 and AT8.
Figure 5
Figure 5
Phosphorylated BRCA1 is localized in some cases of AD to both nuclei as well as some NFT (B). In adjacent serial sections stained for BRCA1 (A), many of the cells containing NFT (arrows) also contain pBRCA1 (B). * denotes landmark vessel.
See this image and copyright information in PMC

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