ADIPONECTIN DEFICIENCY EXACERBATES WHILE ADIPORON ATTENUATES TAUOPATHY IN MICE WITH HUMAN TAU MUTATION

Introduction: Tauopathy is characterized by the accumulation of intraneuronal hyperphosphorylated tau proteins and the aggregation of neurofibrillary tangles, which is a pathological hallmark of neurodegenerative diseases. Adiponectin (APN), an adipokine secreted from adipocytes, exerts anti-inflammatory effects. Whether APN contributes to tauopathy remains unknown. We aim to study the effects of APN deficiency on cognitive functions and neuropathologies, and evaluate the therapeutic potential of an APN receptor agonist adipoRon, in APN-deficient mice with human tauopathy.
Methods: Cognitive functions of 9-month-old wildtype, APN knockout (APN^-/-) mice, human tau P301S mutation transgenic (Tau^P301S) mice, and APN-deficient tau (Tau^P301S; APN^-/-) mice were examined by novel object recognition (NOR) test. Brain pathologies were analysed by immunofluorescent staining. Single-nucleus RNA sequencing was performed to examine APN-mediated transcriptomic alterations in the brains. The therapeutic effects of adipoRon were assessed by treating 6-month-old Tau^P301S; APN^-/- mice for three months.
Results: Tau^P301S; APN^-/- mice spent less time exploring the novel object than wildtype during the NOR test. The immunoreactivity of hyperphosphorylated tau (AT8) and microglia marker ionized calcium-binding adaptor molecule 1 (Ibal) were elevated in Tau^P301S; APN^-/- mice. Tau^P301S; APN^-/- mice exhibited reduced neuronal nuclei (NeuN) positive neurons and spinophilin positive synapses. Single-nucleus RNA sequencing revealed upregulated microglia-mediated immune response in Tau^P301S; APN^-/- mice compared with Tau^P301S mice. Chronic adipoRon treatment improved cognitive functions, reduced AT8 and Iba1 immunoreactivity, and enhanced NeuN and spinophilin staining intensity in Tau^P301S; APN^-/- mice compared with vehicle treatment. Conclusion: APN deficiency aggravates cognitive impairments and neuropathologies, which are reversed by adipoRon treatment.