Tau deficiency contributes to impaired bone formation via activating PPARγ signaling.

Tau protein is enriched in neuronal axons, it functions as a stabilizer of axonal transportation. Hyperphosphorylation of Tau in the brain results in early-onset Alzheimer's disease (AD), causes remarkable bone loss. Notably, pathological Tau leads to the loss of specific physiological Tau that exaggerates Tau toxicity. However, little was known about the physiological role of Tau in bone homeostasis although it's rarely expressed in peripheral tissues. Here, we provided evidence for brain Tau's role in promoting bone formation. Tau knockout (Tau-/-) mice showed smaller body size and exhibited osteoporotic-like deficit, including reduced trabecular and cortical bone mass, especially in young male Tau-/- mice. Such a deficit is likely due to a decrease in osteoblast (OB)-mediated bone formation, as little change in bone resorption in Tau-/- mice. Further mechanistic studies showed increased PPARγ signaling in the brain of Tau-/- mice, which contributed to chemerin release and CMKLR1upregulation in Tau-/- mice brain. Chemerin neutralization remarkably restored osteogenesis potential. Furthermore, reduced repressive H3K9me2 in Tau-/- mice brain led to decreased enrichment of H3K9me2 at PPARγ promoter and thus increased chemerin production. Moreover, PPARγ inhibitor GW9662 significantly reversed the osteoporotic phenotype of Tau-/- mice. Our results implicated brain Tau acting as a dominant positive regulator in bone mass, and unveiled a potential clinical value of PPARγ inhibition in treatment of AD-associated osteoporotic deficits.