Abstract
Cancer and its treatment are associated with neurotoxic side effects, including cognitive dysfunction, altered functional connectivity in the brain and structural abnormalities in white matter. There is evidence that cancer and its treatment can accelerate aging. Tau is a microtubule associated protein that contributes to microtubule stability thereby playing a key role in neuronal function. Clustering of tau is commonly observed in the aged brain and is related to cognitive decline. We hypothesized that chemotherapy-induced cognitive impairment is associated with accelerated development of tau clustering in the brain as a sign of accelerated aging.We show for the first time that treatment of adult (7–8 month-old) male C57BL/6 mice with cisplatin results in reduced cognitive function and a marked increase in the number of large endogenous tau clusters in the hippocampus when assessed 4 months later. In contrast, we detected only few small tau clusters in the hippocampus of age-matched 11–12 month-old control mice. Astrocyte GFAP expression was increased in close vicinity to the tau clusters in cisplatin-treated mice. We did not detect changes in the microglial marker Iba-1 in the brain of mice treated with cisplatin. The accelerated formation of Tau-1 clusters in cisplatin-treated mice was associated with a decrease in the levels of the post-synaptic marker PSD95 and of the presynaptic marker synaptophysin in the hippocampus.We demonstrate here for the first time that chemotherapy markedly accelerates development of signs of tauopathy and loss of synaptic integrity in the hippocampus. These findings provide a mechanistic link between chemotherapy cognitive decline and accelerated aging in cancer survivors.
Highlights
More than 74% of the 15.5 million cancer survivors in the United States are 60 years old or older (Miller et al, 2016)
We aimed at determining whether the chemotherapeutic cisplatin results in development of signs of accelerated aging in the mouse brain
Our results demonstrate that treatment of adult male mice with cisplatin markedly accelerates brain aging as evidenced by extensive development of endogenous mouse tau clusters in the hippocampus at the age of 11–12 months
Summary
More than 74% of the 15.5 million cancer survivors in the United States are 60 years old or older (Miller et al, 2016). In at least a subset of cancer survivors, there is evidence for accelerated biological aging (Henderson et al, 2014). A study by Carroll et al identified a relation between measures of biological aging and cognitive performance in breast cancer survivors (Carroll et al, 2019). Functional neuroimaging studies identified signs of accelerated aging of the brain in cancer survivors (Kesler et al, 2013, 2017). It remains to be determined whether the accelerated aging observed in patients is the result of cancer and/or its treatment
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