Distinct Therapeutic Mechanisms of Tau Antibodies

Funk, Ken; Mirbaha, Hilda; Jiang, Hong; Holtzman, David M.; Diamond, Marc I.

doi:10.1074/jbc.m115.657924

Cited by 95 publications

(59 citation statements)

References 47 publications

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“…Building on these findings, in our bioinformatics 'network' based analysis, we found that both LRRK2 and TBKBP1 interact with genes within the HLA region ( Figure 3). Further, physical interactions between MAPT and the HLA network are compatible with research suggesting that under different conditions reactive microglia can either drive or mitigate tau pathology [47,48]. MAPT mutations, which disrupt the normal binding of tau protein to tubulin, account for a large proportion of familial FTD cases [49].…”

Section: Discussionsupporting

confidence: 71%

Immune-related genetic enrichment in frontotemporal dementia

Broce

Karch²,

Wen³

et al. 2017

Preprint

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Section: Discussionsupporting

confidence: 71%

Immune-related genetic enrichment in frontotemporal dementia

Broce

Karch²,

Wen³

et al. 2017

Preprint

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“…In mouse models of tau-dependent neurodegeneration, passive immunization with anti-tau monoclonal antibodies has been shown to reduce age-dependent tau pathology, including NFTs, neurodegeneration and behavioral impairment (Asuni et al, 2007; Bi et al, 2011; Boutajangout et al, 2011; Chai et al, 2011; Yanamandra et al, 2013). Furthermore, two different antibodies (HJ8.5 and HJ9.4) were able to increase tau clearance via microglia and a parallel block of tau uptake into neurons, in a size-dependent manner (Funk et al, 2015). Still, whether microglia will undergo neurodegeneration after tau uptake or whether these cells will actively function in later stages remains unclear.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Tau Hyperphosphorylation and Dystrophic Microglia in the Common Marmoset

Rodríguez-Callejas

Fuchs

Pérez-Cruz

2016

Front. Aging Neurosci.

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Common marmosets (Callithrix jacchus) have recently gained popularity in biomedical research as models of aging research. Basically, they confer advantages from other non-human primates due to their shorter lifespan with onset of appearance of aging at 8 years. Old marmosets present some markers linked to neurodegeneration in the brain such as amyloid beta (Aβ)1-42 and Aβ1-40. However, there are no studies exploring other cellular markers associated with neurodegenerative diseases in this non-human primate. Using immunohistochemistry, we analyzed brains of male adolescent, adult, old, and aged marmosets. We observed accumulation of Aβ1-40 and Aβ1-42 in the cortex of aged subjects. Tau hyperphosphorylation was already detected in the brain of adolescent animals and increased with aging in a more fibrillary form. Microglia activation was also observed in the aging process, while a dystrophic phenotype accumulates in aged subjects. Interestingly, dystrophic microglia contained hyperphosphorylated tau, but active microglia did not. These results support previous findings regarding microglia dysfunctionality in aging and neurodegenerative diseases as Alzheimer’s disease. Further studies should explore the functional consequences of these findings to position this non-human primate as animal model of aging and neurodegeneration.

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“…Measuring cells’ capacity to internalize various tau fractions and recombinant tau to monitor the uptake and spread of tau pathology has been reported using more conventional techniques [11,16,38–40], as well as with flow cytometry [29,30,41–43]. However, such measurements have not been previously combined with analysis of tau antibody uptake.…”

Section: Discussionmentioning

confidence: 99%

Internalization of tau antibody and pathological tau protein detected with a flow cytometry multiplexing approach

Shamir

Rosenqvist

Rasool

et al. 2016

Alzheimer's & Dementia

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INTRODUCTION Tau immunotherapy has emerged as a promising approach to clear tau aggregates from the brain. Our previous findings suggest that tau antibodies may act outside and within neurons to promote such clearance. METHODS We have developed an approach using flow cytometry, a human neuroblastoma cell model overexpressing tau with the P301L mutation, and paired helical filament (PHF)-enriched pathological tau to effectively screen uptake and retention of tau antibodies in conjunction with PHF. RESULTS The flow cytometry approach correlates well with Western blot analysis to detect internalized antibodies in naïve and transfected SH-SY5Y cells (r2=0.958, and r2=0.968, p=0.021 and p=0.016, respectively). In transfected cells, more antibodies are taken up/retained as pathological tau load increases, both under co-treated conditions and when the cells are pre-treated with PHF prior to antibody administration (r2=0.999 and r2=0.999, p=0.013 and p=0.011, respectively). DISCUSSION This approach allows rapid in vitro screening of antibody uptake and retention in conjunction with pathological tau protein before more detailed studies in animals or other more complex model systems.

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Distinct Therapeutic Mechanisms of Tau Antibodies

Cited by 95 publications

References 47 publications

Immune-related genetic enrichment in frontotemporal dementia

Immune-related genetic enrichment in frontotemporal dementia

Evidence of Tau Hyperphosphorylation and Dystrophic Microglia in the Common Marmoset

Internalization of tau antibody and pathological tau protein detected with a flow cytometry multiplexing approach

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