title: Loss of tau rescues inflammation-mediated neurodegeneration.
abstract: Neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease (AD) and related tauopathies. Activated microglia spatially coexist with microtubule-associated protein tau (Mapt or tau)-burdened neurons in the brains of human AD and non-AD tauopathies. Numerous studies have suggested that neuroinflammation precedes tau pathology and that induction or blockage of neuroinflammation via lipopolysaccharide (LPS) or anti-inflammatory compounds (such as FK506) accelerate or block tau pathology, respectively in several animal models of tauopathy. We have previously demonstrated that microglia-mediated neuroinflammation via deficiency of the microglia-specific chemokine (fractalkine) receptor, CX3CR1, promotes tau pathology and neurodegeneration in a mouse model of LPS-induced systemic inflammation. Here, we demonstrate that tau mediates the neurotoxic effects of LPS in Cx3cr1 (-/-) mice. First, Mapt (+/+) neurons displayed elevated levels of Annexin V (A5) and TUNEL (markers of neurodegeneration) when co-cultured with LPS-treated Cx3cr1 (-/-)microglia, which is rescued in Mapt (-/-) neurons. Second, a neuronal population positive for phospho-S199 (AT8) tau in the dentate gyrus is also positive for activated or cleaved caspase (CC3) in the LPS-treated Cx3cr1 (-/-) mice. Third, genetic deficiency for tau in Cx3cr1 (-/-) mice resulted in reduced microglial activation, altered expression of inflammatory genes and a significant reduction in the number of neurons positive for CC3 compared to Cx3cr1 (-/-)mice. Finally, Cx3cr1 (-/-)mice exposed to LPS displayed a lack of inhibition in an open field exploratory behavioral test, which is rescued by tau deficiency. Taken together, our results suggest that pathological alterations in tau mediate inflammation-induced neurotoxicity and that deficiency of Mapt is neuroprotective. Thus, therapeutic approaches toward either reducing tau levels or blocking neuroinflammatory pathways may serve as a potential strategy in treating tauopathies.
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico Albuquerque, NM, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Maphis
authors.affiliation: Department of Neurosciences, Cleveland Clinic Foundation Cleveland, OH, USA.
authors.forename: Guixiang
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Neurosciences, Cleveland Clinic Foundation Cleveland, OH, USA.
authors.forename: Olga N
authors.initials: ON
authors.lastname: Kokiko-Cochran
authors.affiliation: Department of Biology, University of Texas at San Antonio San Antonio, TX, USA.
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Cardona
authors.affiliation: Biogen Idec Cambridge, MA, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.affiliation: Department of Neurosciences, Cleveland Clinic Foundation Cleveland, OH, USA.
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Lamb
authors.affiliation: Department of Molecular Genetics and Microbiology, University of New Mexico Albuquerque, NM, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Bhaskar
keywords: Alzheimer's disease; CX3CR1; microglia; microtubule associated protein tau (MAPT); neurodegeneration; neuroinflammation; tau protein; tauopathies