Microglial activation and tau propagate jointly across Braak stages

Pascoal, Tharick A.; Benedet, Andréa Lessa; Ashton, Nicholas J.; Kang, Min Su; Therriault, Joseph; Chamoun, Mira; Savard, Mélissa; Lussier, Firoza Z; Tissot, Cécile; Karikari, Thomas K.; Ottoy, Julie; Mathotaarachchi, Sulantha; Stevenson, Jenna; Massarweh, Gassan; Schöll, Michael; Leon, Mony J. de; Soucy, Jean‐Paul; Edison, Paul; Blennow, Kaj; Zetterberg, Henrik; Gauthier, Serge; Rosa‐Neto, Pedro

doi:10.1038/s41591-021-01456-w

Cited by 260 publications

(198 citation statements)

References 82 publications

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“…Whether the reduction in pTau reduces microgliosis or a reduction in microgliosis drives the reduction in pTau, is unclear. A recent study showed that amyloid potentiates microgliosis, which in turn drives tau pathology in the human AD brains [ 80 ]. Future work looking at the effects of these biologic TNF-α inhibitors in mouse models that combine both amyloid and tau pathology, along with the use of CSF1R inhibitors to deplete microglia, will allow us to elucidate the role of microglia-derived TNF-α in the protective effects of these biologic TNF-α inhibitors on both amyloid and tau pathology.…”

Section: Discussionmentioning

confidence: 99%

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Yang

Simanauskaite

et al. 2021

J Neuroinflammation

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Background Tumor necrosis factor-α (TNF-α) plays a central role in Alzheimer’s disease (AD) pathology, making biologic TNF-α inhibitors (TNFIs), including etanercept, viable therapeutics for AD. The protective effects of biologic TNFIs on AD hallmark pathology (Aβ deposition and tau pathology) have been demonstrated. However, the effects of biologic TNFIs on Aβ-independent tau pathology have not been reported. Existing biologic TNFIs do not cross the blood–brain barrier (BBB), therefore we engineered a BBB-penetrating biologic TNFI by fusing the extracellular domain of the type-II human TNF-α receptor (TNFR) to a transferrin receptor antibody (TfRMAb) that ferries the TNFR into the brain via receptor-mediated transcytosis. The present study aimed to investigate the effects of TfRMAb-TNFR (BBB-penetrating TNFI) and etanercept (non-BBB-penetrating TNFI) in the PS19 transgenic mouse model of tauopathy. Methods Six-month-old male and female PS19 mice were injected intraperitoneally with saline (n = 12), TfRMAb-TNFR (1.75 mg/kg, n = 10) or etanercept (0.875 mg/kg, equimolar dose of TNFR, n = 10) 3 days/week for 8 weeks. Age-matched littermate wild-type mice served as additional controls. Blood was collected at baseline and 8 weeks for a complete blood count. Locomotion hyperactivity was assessed by the open-field paradigm. Brains were examined for phosphorylated tau lesions (Ser202, Thr205), microgliosis, and neuronal health. The plasma pharmacokinetics were evaluated following a single intraperitoneal injection of 0.875 mg/kg etanercept or 1.75 mg/kg TfRMAb-TNFR or 1.75 mg/kg chronic TfRMAb-TNFR dosing for 4 weeks. Results Etanercept significantly reduced phosphorylated tau and microgliosis in the PS19 mouse brains of both sexes, while TfRMAb-TNFR significantly reduced these parameters in the female PS19 mice. Both TfRMAb-TNFR and etanercept treatment improved neuronal health by significantly increasing PSD95 expression and attenuating hippocampal neuron loss in the PS19 mice. The locomotion hyperactivity in the male PS19 mice was suppressed by chronic etanercept treatment. Equimolar dosing resulted in eightfold lower plasma exposure of the TfRMAb-TNFR compared with etanercept. The hematological profiles remained largely stable following chronic biologic TNFI dosing except for a significant increase in platelets with etanercept. Conclusion Both TfRMAb-TNFR (BBB-penetrating) and non-BBB-penetrating (etanercept) biologic TNFIs showed therapeutic effects in the PS19 mouse model of tauopathy.

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Section: Discussionmentioning

confidence: 99%

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Yang

Simanauskaite

et al. 2021

J Neuroinflammation

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“…The application of new disease-modifying treatment such as immunotherapy will likely require screening in prodromal patients for pathological evidence, e.g., cerebral Aβ, tau, or α-synuclein accumulation, and monitoring of treatment effects ( Sevigny et al, 2016 ; Boxer et al, 2019 ; Rabinovici et al, 2019 ). In addition, proteinopathy imaging combined with PET for synaptic loss, mitochondria dysfunction, and neuroinflammation (e.g., astrocytosis and microgliosis) enables a more comprehensive understanding of the mechanism underlying neurodegeneration associated with proteinopathies ( Calsolaro et al, 2021 ; Pascoal et al, 2021 ; Zhou R. et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Recent Developments in Positron Emission Tomography Tracers for Proteinopathies Imaging in Dementia

Nitsch

2022

Front. Aging Neurosci.

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An early detection and intervention for dementia represent tremendous unmet clinical needs and priorities in society. A shared feature of neurodegenerative diseases causing dementia is the abnormal accumulation and spreading of pathological protein aggregates, which affect the selective vulnerable circuit in a disease-specific pattern. The advancement in positron emission tomography (PET) biomarkers has accelerated the understanding of the disease mechanism and development of therapeutics for Alzheimer’s disease and Parkinson’s disease. The clinical utility of amyloid-β PET and the clinical validity of tau PET as diagnostic biomarker for Alzheimer’s disease continuum have been demonstrated. The inclusion of biomarkers in the diagnostic criteria has introduced a paradigm shift that facilitated the early and differential disease diagnosis and impacted on the clinical management. Application of disease-modifying therapy likely requires screening of patients with molecular evidence of pathological accumulation and monitoring of treatment effect assisted with biomarkers. There is currently still a gap in specific 4-repeat tau imaging probes for 4-repeat tauopathies and α-synuclein imaging probes for Parkinson’s disease and dementia with Lewy body. In this review, we focused on recent development in molecular imaging biomarkers for assisting the early diagnosis of proteinopathies (i.e., amyloid-β, tau, and α-synuclein) in dementia and discussed future perspectives.

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“…Thus here we discuss briefly the recent development in neuroinflammation imaging in AD amyloidosis animal models. Neuroinflammation plays an important role in the pathogenesis of AD and appears early in the disease development [181][182][183]. Microglia are the resident macrophages in the central nervous system, engulf Aβ plaques and are important for maintaining the brain homeostasis [183,184].…”

Section: Neuroinflammation Imagingmentioning

confidence: 99%

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

Ni¹

2021

Preprint

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Animal models of Alzheimer’s disease amyloidosis that recapitulate cerebral amyloid-beta pathology have been widely used in preclinical research, and have greatly enabled the mechanistic understanding of Alzheimer’s disease and the development of therapeutics. Comprehensive deep phenotyping of the pathophysiological and biochemical features in these animal models are essential. Recent advances in positron emission tomography have allowed the non-invasive visualization of the alterations in the brain of animal models as well as in patients with Alzheimer’s disease, These tools have facilitated our understanding of disease mechanisms, and provided longitudinal monitoring of treatment effect in animal models of Alzheimer’s disease amyloidosis. In this review, we focus on recent positron emission tomography studies of cerebral amyloid-beta accumulation, hypoglucose metabolism, synaptic and neurotransmitter receptor deficits (cholinergic and glutamatergic system), blood-brain barrier impairment and neuroinflammation (microgliosis and astrocytosis) in animal models of Alzheimer’s disease amyloidosis. We further propose the emerging targets and tracers for reflecting the pathophysiological changes, and discuss outstanding challenges in disease animal models and future outlook in on-chip characterization of imaging biomarkers towards clinical translation.

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Microglial activation and tau propagate jointly across Braak stages

Cited by 260 publications

References 82 publications

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Biologic TNF-α inhibitors reduce microgliosis, neuronal loss, and tau phosphorylation in a transgenic mouse model of tauopathy

Recent Developments in Positron Emission Tomography Tracers for Proteinopathies Imaging in Dementia

Positron Emission Tomography in Animal Models of Alzheimer’s Disease Amyloidosis

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