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.

ATP13A2 is a lysosomal protein involved in polyamine transport with loss of function mutations associated with multiple neurodegenerative conditions. These include early onset Parkinson’s disease, Kufor-Rakeb Syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. While ATP13A2 mutations may result in clinical heterogeneity, the basal ganglia appear to be impacted in the majority of cases. The basal ganglia is particularly vulnerable to environmental exposures such as heavy metals, pesticides, and industrial agents which are also established risk factors for many neurodegenerative conditions. Not surprisingly then, impaired function of ATP13A2 has been linked to heavy metal toxicity including manganese, iron, and zinc. This review discusses the role of ATP13A2 in basal ganglia function and dysfunction, potential common pathological mechanisms in ATP13A2-related disorders, and how gene x environment interactions may contribute to basal ganglia dysfunction.