Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer‘s disease

Collin, Ludovic; Bohrmann, Bernd; Göpfert, Ulrich; Oroszlan-Szovik, Krisztina; Ozmen, Laurence; Grüninger, Fiona

doi:10.1093/brain/awu213

Cited by 181 publications

(152 citation statements)

References 54 publications

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“…It has been shown that targeting the pS422 tau epitope with active vaccination decreases levels of insoluble phosphorylated tau and improves behavioral performance in transgenic mouse model of tauopathy [142]. Moreover, in a transgenic mouse model of AD, anti-tau pS422 antibodies are able to reduce accumulation of tau and induce its clearance via lysosomal pathways [88]. Anti-tau antibodies are internalized by neurons with tau aggregates via interaction with Fcγ receptors, and this internalization leads to the clearance of tau pathology in primary neurons [150], a mechanism that is probably shared with antibodies against α-syn (Fig.…”

Section: Immunotherapy Targeting Taumentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Section: Immunotherapy Targeting Taumentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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“…In Alzheimer disease, abnormal phosphorylation, misfolding and aggregation of tau lead to neurofibrillary tangle formation, and ultimately to neuronal cell death. 27 A proposed mode of action of the anti-tau/pS422 antibody Rb86 is that it binds to membrane-associated tau/pS422, upon which the antibody-antigen complexes are internalized and cleared within the cell, so that the neurodegenerative pathology of tau is ameliorated. An alignment of the VH and VL sequences of CD81K04, CD81K13 and Rb86 is given in Fig.…”

Section: Introductionmentioning

confidence: 99%

VH-VL orientation prediction for antibody humanization candidate selection: A case study

Bujotzek¹,

Lipsmeier²,

Harris³

et al. 2015

mAbs

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Antibody humanization describes the procedure of grafting a non-human antibody's complementaritydetermining regions, i.e., the variable loop regions that mediate specific interactions with the antigen, onto a b-sheet framework that is representative of the human variable region germline repertoire, thus reducing the number of potentially antigenic epitopes that might trigger an anti-antibody response. The selection criterion for the so-called acceptor frameworks (one for the heavy and one for the light chain variable region) is traditionally based on sequence similarity. Here, we propose a novel approach that selects acceptor frameworks such that the relative orientation of the 2 variable domains in 3D space, and thereby the geometry of the antigen-binding site, is conserved throughout the process of humanization. The methodology relies on a machine learning-based predictor of antibody variable domain orientation that has recently been shown to improve the quality of antibody homology models. Using data from 3 humanization campaigns, we demonstrate that preselecting humanization variants based on the predicted difference in variable domain orientation with regard to the original antibody leads to subsets of variants with a significant improvement in binding affinity.

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“…In addition, passive immunization has also been investigated using a humanized monoclonal antibody targeting pS422 phospho-tau. In AD mice, chronic administration of this antibody reduced hyperphosphorylated tau accumulation [126], although clinical studies with this antibody were recently discontinued in phase 1 (see Table 1). …”

Section: Update On Dementiamentioning

confidence: 99%

Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease

Torres¹,

Busquets²,

Escribá³

2016

Update on Dementia

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Alzheimer's disease (AD) is a neurodegenerative disorder that causes severe and progressive cognitive impairment. The discovery of specific mutations related to AD supported the amyloid cascade hypothesis, which postulates that the accumulation of the amyloid-β (Aβ) peptide triggers neuronal death and dementia. However, most drugs that aim to prevent Aβ accumulation or tau phosphorylation have consistently failed in clinical trials. This would suggest that the amyloid pathology lies downstream of (an)other cellular event(s) that is/are responsible for AD pathogenesis. In this context, several lipid alterations have been described in the brain and in peripheral fluids of patients with AD, suggesting the involvement of lipids in the etiology of this condition. Indeed, the central nervous system (CNS) has the highest lipid content in the body, next to adipose tissue, and it is thought that normalization of brain membrane lipid levels would revert AD-related pathogenic events. In this sense, novel hydroxylated derivatives of docosahexaenoic acid (DHA) such as natural resolvins or synthetic hydroxy-DHA (HDHA, DHALifort) can modulate membrane lipid composition and show remarkable beneficial effects on AD hallmarks, such as prevention of amyloid production and tau phosphorylation, and cognitive restoration in animal models. Therefore, normalization of the neuronal lipid environment by hydroxyl-DHA and/or other lipids may constitute a promising therapy for AD treatment, memory loss and, possibly, other types of dementia.

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Neuronal uptake of tau/pS422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer‘s disease

Cited by 181 publications

References 54 publications

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

VH-VL orientation prediction for antibody humanization candidate selection: A case study

Brain Lipids in the Pathophysiology and Treatment of Alzheimer’s Disease

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