Tau immunotherapy is associated with glial responses in FTLD-tau

Kim, Boram; Mikytuck, Bailey; Suh, EunRan; Gibbons, Garrett S.; Deerlin, Vivianna M. Van; Vaishnavi, Sanjeev; Spindler, Meredith; Massimo, Lauren; Grossman, Murray; Trojanowski, John Q.; Irwin, David J.; Lee, Edward B.

doi:10.1007/s00401-021-02318-y

Cited by 34 publications

(13 citation statements)

References 32 publications

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“…ABBV-8E12 (tilavonemab) and BIIB092 (gosuranemab), which bind tau at the N-terminal side, failed to show efficacy in PSP patients in two phase 2 clinical trials [209,210]. However, decreased CSF free tau and accumulation of tau in lysosomes of emerging perivascular vesicular astrocytes proved that the binding happens as anticipated [209,211]. Reasons for futility in clinical trials include difficulties in earlier diagnosis of PSP, especially preclinical stages, noneffective epitopes and extracellular targeting [210].…”

Section: Tau Immunizationmentioning

confidence: 99%

Tauopathies: new perspectives and challenges

Zhang

Liu

et al. 2022

Mol Neurodegeneration

158

114

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Background Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions. Main body Clinically, tauopathies can present with a range of phenotypes that include cognitive/behavioral-disorders, movement disorders, language disorders and non-specific amnestic symptoms in advanced age. Pathologically, tauopathies can be classified based on the predominant tau isoforms that are present in the inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) and blood-based tau biomarkers have the potential to be used as a routine diagnostic strategy and in the evaluation of patients with tauopathies. As tauopathies are strongly linked neuropathologically and genetically to tau protein abnormalities, there is a growing interest in pursuing of tau-directed therapeutics for the disorders. Here we synthesize emerging lessons on tauopathies from clinical, pathological, genetic, and experimental studies toward a unified concept of these disorders that may accelerate the therapeutics. Conclusions Since tauopathies are still untreatable diseases, efforts have been made to depict clinical and pathological characteristics, identify biomarkers, elucidate underlying pathogenesis to achieve early diagnosis and develop disease-modifying therapies.

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Section: Tau Immunizationmentioning

confidence: 99%

Tauopathies: new perspectives and challenges

Zhang

Liu

et al. 2022

Mol Neurodegeneration

158

114

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“…A phase II trial in progressive supranuclear palsy showed that the unbound N-terminal tau in CSF was decreased by 98% in the gosuranemab group and increased by 11% in the placebo group, but the N-terminal tau neutralization does not translate into clinical efficacy (NCT03068468) [ 72 ]. Recently, Kim and his colleagues examined the brain tissues of three individuals receiving gosuranemab and found that gosuranemab treatment may be associated with glial responses including accumulation of tau within astrocytic lysosomes [ 73 ]. However, the phase II study of gosuranemab in participants with early AD was terminated due to the lack of efficacy in slowing cognitive and functional impairment following the placebo-controlled period readout [ 74 ].…”

Section: Immunotherapies Based On Tau Proteinmentioning

confidence: 99%

Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond

Song

Shi

Zhang

et al. 2022

Transl Neurodegener

145

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Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly worldwide. However, the complexity of AD pathogenesis leads to discrepancies in the understanding of this disease, and may be the main reason for the failure of AD drug development. Fortunately, many ongoing preclinical and clinical studies will continually open up avenues to unravel disease mechanisms and guide strategies for AD diagnosis and drug development. For example, immunotherapeutic strategies targeting amyloid-β (Aβ) and tau proteins were once deemed almost certainly effective in clinical treatment due to the excellent preclinical results. However, the repeated failures of clinical trials on vaccines and humanized anti-Aβ and anti-tau monoclonal antibodies have resulted in doubts on this strategy. Recently, a new anti-Aβ monoclonal antibody (Aducanumab) has been approved by the US Food and Drug Administration, which brings us back to the realization that immunotherapy strategies targeting Aβ may be still promising. Meanwhile, immunotherapies based on other targets such as tau, microglia and gut-brain axis are also under development. Further research is still needed to clarify the forms and epitopes of targeted proteins to improve the accuracy and effectiveness of immunotherapeutic drugs. In this review, we focus on the immunotherapies based on Aβ, tau and microglia and their mechanisms of action in AD. In addition, we present up-to-date advances and future perspectives on immunotherapeutic strategies for AD.

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“…A glial profiling study demonstrated enrichment of astrocytic transcripts in tau-related FTLD degeneration [125]. In humans, tau immunotherapy results have been shown to be associated with glial responses in FTLD-tau [126].…”

Section: Discussionmentioning

confidence: 99%

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

Kecheliev

Boss

Maheshwari

et al. 2022

Preprint

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Neurovascular-glymphatic dysfunction plays an important role in Alzheimer’s disease and has been analyzed mainly in association with amyloid-beta (Aβ) pathology. The neurovascular-glymphatic link with tauopathies has not been well elucidated. Here, we aimed to investigate the alterations in the neurovasculature and map the aquaporin 4 (AQP4) distribution and depolarization associated with tau and Aβ. Perfusion, susceptibility weighted imaging and structural magnetic resonance imaging (MRI) were performed in the pR5 P301L mouse model of 4-repeat tau and the arcAβ mouse model of amyloidosis. Immunofluorescence staining was performed using antibodies against AQP4, CD31, astroglia (GFAP, s100β), phospho-tau (AT-8) and Aβ (6E10) in brain tissue slices from P301L, arcAβ and nontransgenic mice. P301L mice showed regional atrophy, preserved cerebral blood flow and reduced cerebral vessel density compared to nontransgenic mice, while arcAβ mice showed cerebral microbleeds and reduced cerebral vessel density. AQP4 depolarization and peri-tau enrichment in the hippocampus and increased AQP4 levels in the forebrain and hippocampus were detected in P301L mice compared to nontransgenic mice. In comparison, cortical AQP4 depolarization and cortical/hippocampal peri-plaque increases were observed in arcAβ mice. Increased s100β-GFAP fluorescence intensities indicative of reactive astrocytes were detected surrounding tau inclusions in P301L mice and Aβ plaques in arcAβ mice. In conclusion, we observed a divergent region-specific AQP4 increase and association with phospho-tau and Aβ pathologies.

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Tau immunotherapy is associated with glial responses in FTLD-tau

Cited by 34 publications

References 32 publications

Tauopathies: new perspectives and challenges

Tauopathies: new perspectives and challenges

Immunotherapy for Alzheimer’s disease: targeting β-amyloid and beyond

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

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