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.

Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis

“…Tau absence confers neuroprotection in several models of neuronal damage, such as traumatic brain injury (Cheng et al , 2014), neuroinflammation (Maphis et al , 2015), amyloid β‐mediated excitotoxicity (Roberson et al , 2007, 2011; Ittner et al , 2010; Vossel et al , 2010), and epilepsy (Holth et al , 2013), among others. Given that acute stress negatively affects AHN (Gould et al , 1992) and considering the neuroprotection exerted by the lack of Tau in the aforementioned models, we addressed whether the Porsolt test would cause similar detrimental effects in Tau −/− and WT mice.…”

Dysfunctional Sensory Modalities, Locus Coeruleus, and Basal Forebrain: Early Determinants that Promote Neuropathogenesis of Cognitive and Memory Decline and Alzheimer’s Disease

“…However, tau pathology in 3xTg-AD transgenic mice may develop independently of Ab generation (Ghosal et al 2009;Winton et al 2011). Finally, either reducing tau (Sigurdsson 2008;Chai et al 2011;Boutajangout et al 2011) or blocking neuroinflammatory pathways may serve as therapeutic targets to attenuate neurotoxicity/neurodegeneration and cognitive decline (Iadecola et al 1999;Ishizawa and Dickson 2001;Gabbita et al 2012;Maphis et al 2015b;Daulatzai 2016b, c).…”

Novel Key Players in the Development of Tau Neuropathology: Focus on the 5-Lipoxygenase

“…Misfolded truncated tau is reported to activate the innate immune response via activation of the MAPK kinase pathway and to induce the release nitric oxide and other powerful pro-inflammatory cytokines (i.e., Interleukin-1β, Interleukin-6 and Tumor Necrosis Factor-α) [25, 26]. Finally, loss of tau in neurons and microglia provides protection against lipopolysaccharide-induced neurotoxicity, which under normal conditions triggers tau hyper-phosphorylation, tau pathology and ultimately cell loss and neurodegeneration [27]. …”