Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy

Bemiller, Shane M.; Maphis, Nicole; Formica, Shane; Wilson, Gina N.; Miller, Crystal; Xu, Guixiang; Kokiko-Cochran, Olga N.; Cannon, Judy L.; Crish, Samuel D.; Cardona, Astrid E.; Lamb, Bruce T.; Bhaskar, Kiran

doi:10.1186/s12974-018-1310-6

Cited by 18 publications

(19 citation statements)

References 36 publications

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“…Cx3cl1 overexpression in a tauopathy mouse model decreases tau hyperphosphorylation of tau, neurodegeneration, and cognitive deficits – likely by suppressing microglial activation via Cx3cr1 [89, 221]. The opposite effect was observed in CX3CR1 receptor knockouts [22, 29, 178, 199]. Curiously, knockout of tau also rescued inflammation-mediated neurodegeneration in mice lacking the Cx3cr1 receptor [198].…”

Section: Bidirectional Effects Of Tau Pathology and Microglial Neuroimentioning

confidence: 99%

Intersection of pathological tau and microglia at the synapse

Vogels

Murgoci

Hromádka

2019

acta neuropathol commun

146

141

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Tauopathies are a heterogenous class of diseases characterized by cellular accumulation of aggregated tau and include diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy and chronic traumatic encephalopathy. Tau pathology is strongly linked to neurodegeneration and clinical symptoms in tauopathy patients. Furthermore, synapse loss is an early pathological event in tauopathies and is the strongest correlate of cognitive decline. Tau pathology is additionally associated with chronic neuroinflammatory processes, such as reactive microglia, astrocytes, and increased levels of pro-inflammatory molecules (e.g. complement proteins, cytokines). Recent studies show that as the principal immune cells of the brain, microglia play a particularly important role in the initiation and progression of tau pathology and associated neurodegeneration. Furthermore, AD risk genes such as Triggering receptor expressed on myeloid cells 2 ( TREM2 ) and Apolipoprotein E ( APOE ) are enriched in the innate immune system and modulate the neuroinflammatory response of microglia to tau pathology. Microglia can play an active role in synaptic dysfunction by abnormally phagocytosing synaptic compartments of neurons with tau pathology. Furthermore, microglia are involved in synaptic spreading of tau – a process which is thought to underlie the progressive nature of tau pathology propagation through the brain. Spreading of pathological tau is also the predominant target for tau-based immunotherapy. Active tau vaccines, therapeutic tau antibodies and other approaches targeting the immune system are actively explored as treatment options for AD and other tauopathies. This review describes the role of microglia in the pathobiology of tauopathies and the mechanism of action of potential therapeutics targeting the immune system in tauopathies.

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Section: Bidirectional Effects Of Tau Pathology and Microglial Neuroimentioning

confidence: 99%

Intersection of pathological tau and microglia at the synapse

Vogels

Murgoci

Hromádka

2019

acta neuropathol commun

146

141

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“…For instance, disrupting FKN signaling has been shown to be beneficial in stroke and models of amyloid deposition [7–10] while detrimental in tauopathy and Parkinson’s disease (PD) models [11–13]. Reports from neuropathic pain and Alzheimer’s disease (AD) models have further shown that there may be differential signaling elicited by full-length vs soluble FKN [14–16]. Here, we focus on the effects of FKN signaling in AD models as well as the differential effects of full length FKN signaling as compared to soluble FKN signaling.…”

Section: Introductionmentioning

confidence: 99%

“…They argued that it is therefore the membrane-bound variant of FKN, and not a soluble ligand, that impacts amyloid pathology. In a more recent report, Bemiller et al [14] observed an increased susceptibility to LPS-induced tauopathy and microglial activation in the mice expressing only ckFKN. Furthermore, they show that hTau mice expressing ckFKN (hTau/CX3CL1 105Δ ) had similar phospho-tau pathology and cognitive deficits as hTau; Cx3cl1−/− mice, both of which had significantly greater phospho-tau pathology and cognitive deficits than hTau mice expressing endogenous FKN.…”

Section: Introductionmentioning

confidence: 99%

Neuroinflammation and fractalkine signaling in Alzheimer’s disease

Finneran

Nash

2019

J Neuroinflammation

110

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Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder, and the most common form of dementia. As the understanding of AD has progressed, it is now believed that AD is an amyloid-initiated tauopathy with neuroinflammation serving as the link between amyloid deposition, tau pathology, and neurodegeneration. As microglia are the main immune effectors in the central nervous system, they have been the focus of attention in studies investigating the neuroinflammatory component of AD. Therefore, recent work has focused on immunomodulators, which can alter microglial activation without suppressing activity, as potential therapeutics for AD. Fractalkine (CX3CL1; FKN), a unique chemokine with a one-to-one relationship with its receptor, signals through its cognate receptor (CX3CR1) to reduce expression of pro-inflammatory genes in activated microglia. Disrupting FKN signaling has opposing effects on the two hallmark pathologies of AD, but over-expressing a soluble FKN has been shown to reduce tau pathology while not altering amyloid pathology. Recently, differential signaling has been reported when comparing two cleavage variants of soluble FKN. These differential effects may explain recent studies reporting seemingly conflicting results regarding the effect of FKN over expression on AD pathologies.

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“…In contrast, Bemiller et al showed the opposite results in an hTau mouse and concluded that sCX3CL1 is not protective. The authors of that work suggested that the discrepancies between these studies are due to the experimental approach (recombinant adeno-associated virus (rAAV) vector-mediated overexpression vs. transgenic mouse), the differences in sCX3CL1 structure (presence or not of mucin stalk), and the tauopathy mouse model used (rTg4510 vs. hTau) [ 246 ]. However, the CX3CL1 intracellular fragment enhances neurogenesis, improves cognitive function, and increases the lifespan.…”

Section: Neuron–microglia Crosstalk: Implications Of the Cx3cl1–cxmentioning

confidence: 99%

Microglia in Alzheimer’s Disease in the Context of Tau Pathology

2020

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Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.

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Genetically enhancing the expression of chemokine domain of CX3CL1 fails to prevent tau pathology in mouse models of tauopathy

Cited by 18 publications

References 36 publications

Intersection of pathological tau and microglia at the synapse

Intersection of pathological tau and microglia at the synapse

Neuroinflammation and fractalkine signaling in Alzheimer’s disease

Microglia in Alzheimer’s Disease in the Context of Tau Pathology

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