Chromatin damage threatens NFT bearing neurons in 3xTg AD mouse model

Neurofibrillary tangles (NFTs) are characteristic of Tau-linked dementias including Alzheimer's Disease (AD), Frontotemporal Dementia, and Niemann Pick Type C Disease. A direct link between NFTs and neuronal cell death has remained elusive. Interestingly, some reports even suggested a lack of correlation between NFTs and neuronal damage markers such as nitrotyroxine, TdT DNA damage, and caspase mediated cell death in AD. Some transgenic mice carrying human mutants of Tau, such as 3xTg AD mice, develop age related neurodegeneration associated with the histological presence of NFTs, and are therefore used as a model for Tau-linked dementias. We used immunohistochemistry and confocal microscopy to analyze fixed brain sections of 21-month-old 3xTg mice. When co-stained with the phospho-tau antibody, PHF1, and the double-break DNA damage marker gamma-H2A.X, we observed that CA1 pyramidal neurons immunoreactive with PHF1 contained bright gamma-H2A.X signal in the form of nuclear foci. Neurons without histological evidence of NFTs in CA1, other hippocampal regions, or cortex lacked these gamma-H2A.X nuclear foci and occasionally displayed diffuse cytoplasmic gamma-H2A.X immunoreactivity. Animals with a greater severity of PHF1 immunoreactivity, quantified by the number of stained neurons, consistently showed increased gamma-H2A.X foci that colocalized with PHF1 immunoreactive cells. The strong correlation between gamma-H2A.X foci and PHF1 signal indicates that chromatin damage occurs in neurons bearing NFTs, suggesting that mechanisms for Tau-induced neuronal toxicity may include non-caspase Apoptosis Inducion Factor (AIF)-mediated programmed cell death. In agreement with our results, it was recently indicated that AIF correlates with NFTs and may mediate neuronal cell death in AD.