Microglia become hypofunctional and release metalloproteases and tau seeds when phagocytosing live neurons with P301S tau aggregates

Brelstaff, Jack; Mason, Matthew; Katsinelos, Taxiarchis; McEwan, William A.; Ghetti, Bernardino; Tolkovsky, Aviva M.; Spillantini, Maria Grazia

doi:10.1126/sciadv.abg4980

Cited by 90 publications

(86 citation statements)

References 64 publications

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“…Tau aggregates caused the neurons to display PtdSer because of reactive oxygen species (ROS) induction [ 50 ], and contact with microglia caused them to release opsonins that enabled the phagocytic process. Interestingly, these microglia released tau aggregates they had ingested with the neurons, while releasing other senescence-associated paracrine factors that caused other microglia to become hypophagocytic, which could exacerbate the development of tauopathy, tau toxicity, and cell death [ 56 , 57 ]. Interestingly, microglial senescence has been associated with tau pathology and neurodegeneration in AD and other tauopathies [ 58 , 59 ] and tau aggregate-associated neuronal senescence has also been implicated in neurodegeneration [ 60 ], although the mechanism of neuronal death has not been defined.…”

Section: Tau Aggregation or Pathology And Non-cell Autonomous Death Mechanismsmentioning

confidence: 99%

Tau aggregation and its relation to selected forms of neuronal cell death

Tolkovsky

Spillantini

2021

Essays in Biochemistry

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How neurons die in neurodegenerative diseases is still unknown. The distinction between apoptosis as a genetically controlled mechanism, and necrosis, which was viewed as an unregulated process, has blurred with the ever-increasing number of necrotic-like death subroutines underpinned by genetically defined pathways. It is therefore pertinent to ask whether any of them apply to neuronal cell death in tauopathies. Although Alzheimer’s disease (AD) is the most prevalent tauopathy, tauopathies comprise an array of over 30 diseases in which the cytoplasmic protein tau aggregates in neurons, and also, in some diseases, in glia. Animal models have sought to distil the contribution of tau aggregation to the cell death process but despite intensive research, no one mechanism of cell death has been unequivocally defined. The process of tau aggregation, and the fibrillar structures that form, touch on so many cellular functions that there is unlikely to be a simple linear pathway of death; as one is blocked another is likely to take the lead. It is timely to ask how far we have advanced into defining whether any of the molecular players in the new death subroutines participate in the death process. Here we briefly review the currently known cell death routines and explore what is known about their participation in tau aggregation-related cell death. We highlight the involvement of cell autonomous and the more recent non-cell autonomous pathways that may enhance tau-aggregate toxicity, and discuss recent findings that implicate microglial phagocytosis of live neurons with tau aggregates as a mechanism of death.

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Section: Tau Aggregation or Pathology And Non-cell Autonomous Death Mechanismsmentioning

confidence: 99%

Tau aggregation and its relation to selected forms of neuronal cell death

Tolkovsky

Spillantini

2021

Essays in Biochemistry

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“…Microglia activation has been shown to occur preceding the tangle formation in tau mice ( Yoshiyama et al, 2007 ). In addition, microglia was activated to engulf neuron containing tau aggregates, turned hypofunctional after phagocytosis, released the seed component of tau aggregates, and, thus, facilitated the spreading of tau in PS19 mice ( Bellucci et al, 2004 ; Brelstaff et al, 2021 ). Thus, imaging of neuroinflammation in tauopathy mice offers crucial dynamic pathophysiological information and potential diagnostic parameter ( Leng and Edison, 2021 ).…”

Section: Neuroinflammation Imagingmentioning

confidence: 99%

Positron Emission Tomography in Animal Models of Tauopathies

Cao

Kong

et al. 2022

Front. Aging Neurosci.

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The microtubule-associated protein tau (MAPT) plays an important role in Alzheimer’s disease and primary tauopathy diseases. The abnormal accumulation of tau contributes to the development of neurotoxicity, inflammation, neurodegeneration, and cognitive deficits in tauopathy diseases. Tau synergically interacts with amyloid-beta in Alzheimer’s disease leading to detrimental consequence. Thus, tau has been an important target for therapeutics development for Alzheimer’s disease and primary tauopathy diseases. Tauopathy animal models recapitulating the tauopathy such as transgenic, knock-in mouse and rat models have been developed and greatly facilitated the understanding of disease mechanisms. The advance in PET and imaging tracers have enabled non-invasive detection of the accumulation and spread of tau, the associated microglia activation, metabolic, and neurotransmitter receptor alterations in disease animal models. In vivo microPET studies on mouse or rat models of tauopathy have provided significant insights into the phenotypes and time course of pathophysiology of these models and allowed the monitoring of treatment targeting at tau. In this study, we discuss the utilities of PET and recently developed tracers for evaluating the pathophysiology in tauopathy animal models. We point out the outstanding challenges and propose future outlook in visualizing tau-related pathophysiological changes in brain of tauopathy disease animal models.

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“…They likely participate in phagoptosis; dark microglia have increased phagocytic inclusions and commonly enwrap processes around shrinking but still viable neuronal elements 90 . Furthermore, Brelstaff et al recently found that when murine microglial cells were co-cultured invitro with viable P301S neurons growing intracellular, human hp-tau filaments, these microglia prematurely phagoptosed the neurons then became senescent 92 . These senescent microglia exhibited increased NF- activation, MMP-3 release, and positive SA--gal staining; additionally, they displayed an hypo-phagocytic capacity, or poor phagoptosis of P301S neurons containing hp-tau aggregates, together with an aberrant release of insoluble hp-tau aggregates into the local environment 92 .…”

Section: Cns Glia Lose Homeostatic Capacity With Agingmentioning

confidence: 99%

“…Furthermore, Brelstaff et al recently found that when murine microglial cells were co-cultured invitro with viable P301S neurons growing intracellular, human hp-tau filaments, these microglia prematurely phagoptosed the neurons then became senescent 92 . These senescent microglia exhibited increased NF- activation, MMP-3 release, and positive SA--gal staining; additionally, they displayed an hypo-phagocytic capacity, or poor phagoptosis of P301S neurons containing hp-tau aggregates, together with an aberrant release of insoluble hp-tau aggregates into the local environment 92 . As cultured human microglial cells also phagoptose PS-exposed, P301S neurons containing hp-tau aggregates 57 , both human and murine senescent microglia likely release and seed insoluble hp-tau aggregates [93][94][95] .…”

Section: Cns Glia Lose Homeostatic Capacity With Agingmentioning

confidence: 99%

“…As cultured human microglial cells also phagoptose PS-exposed, P301S neurons containing hp-tau aggregates 57 , both human and murine senescent microglia likely release and seed insoluble hp-tau aggregates [93][94][95] . Furthermore, Brelstaff et al revealed that conditioned media, isolated from murine microglia and P301S neurons, induced senescence in separate murine microglial cultures 92 . This indicates that secretions from senescent microglia, containing hp-tau, can trigger local, paracrine senescence in other microglia.…”

Section: Cns Glia Lose Homeostatic Capacity With Agingmentioning

confidence: 99%

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The Glial Aging & Senescence Hypothesis of Late-onset Alzheimer’s

Lau¹,

Ramer²,

Tremblay³

2022

Preprint

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Alzheimer’s disease (AD) predominantly occurs as a late-onset form (LOAD), involving neurodegeneration and cognitive decline with progressive memory loss. Over time, risk factors and aging promote accumulation of well-known AD pathologies in oxidative stress, amyloid-beta and tau protein pathology, as well as inflammation. Homeostatic glial functions regulate and suppress these AD pathologies; however, other glial states involve increased pro-inflammatory cytokine release and further pathology accumulation. Different stresses can additionally induce cellular senescence, or an irreversible differentiation process resulting in decreased supportive functions and increased, pro-inflammatory cytokine release. While these pathophysiological underpinnings all contribute to LOAD, they require temporal and mechanistic integration. This perspective hypothesizes that when individuals have threshold senescent glia accumulation, they transition from healthy cognition into mild cognitive impairment and LOAD diagnosis. Particularly, senescent microglia are predicted to represent a final threshold required for the tau pathology burden and spreading that corresponds to sustained neurodegeneration and dementia severity. We first explore age-related decline in glia that promote increases in AD pathologies, and then discuss emerging evidence linking oxidative stress, neurons containing tau pathology, and amyloid-beta to microglia, oligodendrocyte progenitor cell, and astrocyte senescence. Our hypothesis proposes that senescent astrocytes and oligodendrocyte progenitors pressure microglia to phagocytose neurons containing tau pathology. The resulting senescent microglia would form neuritic plaques and induce paracrine senescence transitioning into a progressive clinical dementia presentation. This predictive hypothesis can potentially account for why medications used to treat LOAD fail, as previous treatments have not reduced senescent glial burden. It is also coherent with the predominant hypotheses surrounding LOAD, generates testable hypotheses about LOAD, and increases rationale in testing senolytics as targeted treatments for LOAD arrest and reversal.

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Microglia become hypofunctional and release metalloproteases and tau seeds when phagocytosing live neurons with P301S tau aggregates

Abstract: Microglia change their behavior when eating live neurons containing tau protein aggregates, a hallmark of Alzheimer’s disease.

Cited by 90 publications

References 64 publications

Tau aggregation and its relation to selected forms of neuronal cell death

Tau aggregation and its relation to selected forms of neuronal cell death

Positron Emission Tomography in Animal Models of Tauopathies

The Glial Aging & Senescence Hypothesis of Late-onset Alzheimer’s

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