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Aims Irisin is a hormone cleaved from fibronectin type‐III domain‐containing protein 5 in response to exercise and may be therapeutic in Alzheimer's disease (AD). Irisin is shown to repair damage caused by midlife cardiometabolic risk factors for AD (i.e., diabetes mellitus; hypertension), prevent neural amyloid beta aggregation and reduce neuroinflammation. However, there are no investigations of irisin's effect on AD‐associated tauopathy in the brain. This study begins to address this gap in knowledge. Methods Transgenic htau mice that selectively develop age‐related tauopathy were treated with recombinant irisin (100 µg/kg weekly i.p.) beginning at a pre‐symptomatic age (4 months) to determine if irisin could prevent emergence of early neuropathology. One month later, mice were sacrificed to collect brain tissue and serum. Protein levels of ptau (serine 202), inflammatory cytokine tumour necrosis factor alpha (TNFα) and FNDC5 were quantified using capillary‐based western blotting (Wes). Results Our data show that irisin treatment significantly reduced ptau and TNFα in the hippocampus and serum of female htau mice compared to vehicle‐treated controls. Irisin treatment did not alter ptau levels in male htau hippocampus and appeared to enhance both neural and systemic TNFα levels. Conclusions This study provides the first evidence that enhancing the endogenous hormone irisin may be therapeutic against emerging neuropathology in a tauopathy‐selective AD model. This is important because there are currently no disease‐modifying therapeutics available for AD, and few agents in development address the multiple disease targets irisin appears to—making irisin an intriguing therapeutic candidate for further investigation.

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