Two Novel Tau Antibodies Targeting the 396/404 Region Are Primarily Taken Up by Neurons and Reduce Tau Protein Pathology

Gu, Jiaping; Congdon, Erin E.; Sigurdsson, Einar M.

doi:10.1074/jbc.m113.494922

Cited by 149 publications

(189 citation statements)

References 58 publications

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“…It has previously been demonstrated that antibody receptors FcγRII/III expressed on the surface of neurons in brain slices mediates uptake of uncomplexed anti-tau antibodies (24,25). The internalized antibodies are proposed to interact with cellular tau pools in a compartment that stains positive for markers of the endolysosome.…”

Section: Trim21 Is the Sole Protective Fc Receptor In A Human Neuronamentioning

confidence: 99%

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

McEwan

Falcon

Vaysburd

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

160

163

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Alzheimer's disease (AD) and other neurodegenerative disorders are associated with the cytoplasmic aggregation of microtubuleassociated protein tau. Recent evidence supports transcellular transfer of tau misfolding (seeding) as the mechanism of spread within an affected brain, a process reminiscent of viral infection. However, whereas microbial pathogens can be recognized as nonself by immune receptors, misfolded protein assemblies evade detection, as they are host-derived. Here, we show that when misfolded tau assemblies enter the cell, they can be detected and neutralized via a danger response mediated by tau-associated antibodies and the cytosolic Fc receptor tripartite motif protein 21 (TRIM21). We developed fluorescent, morphology-based seeding assays that allow the formation of pathological tau aggregates to be measured in situ within 24 h in the presence of picomolar concentrations of tau seeds. We found that anti-tau antibodies accompany tau seeds into the cell, where they recruit TRIM21 shortly after entry. After binding, TRIM21 neutralizes tau seeds through the activity of the proteasome and the AAA ATPase p97/VCP in a similar manner to infectious viruses. These results establish that intracellular antiviral immunity can be redirected against host-origin endopathogens involved in neurodegeneration.T he cell's ability to identify intracellular viruses and bacteria relies on the detection of pathogen-associated molecular patterns (PAMPs) by specialized host receptors. Although highly effective at detecting microbial pathogens, this strategy is poorly equipped to identify host-derived pathogenic species such as aggregated proteins. As an alternative to PAMP detection, recent work has demonstrated that mammalian cells can use hostderived serum proteins, which are normally excluded from the cell interior, to target invading viruses and bacteria in the cytosol. For instance, nonenveloped viruses and bacteria carry antibodies with them into the cytoplasm during infection. These translocated antibodies are then sensed by the cytoplasmically expressed antibody receptor TRIM21 (tripartite motif protein 21), which binds with subnanomolar affinity to the antibody Fc domain (1-4). After binding to antibody, TRIM21 triggers a potent neutralization response that inhibits viral infection. Neutralization of infection is accompanied by degradation of viral components, which requires the activity of the proteasome and the molecular unfoldase, valosincontaining protein (VCP) or p97 (1, 5). Detection of viruses and bacteria by TRIM21 does not rely on microbial PAMPs, as model substrates such as antibody-coated latex beads can be bound and detected by TRIM21 (1, 3). We therefore hypothesized that the intracellular innate immune system could be repurposed to recognize and degrade host-derived pathogenic proteins.Microtubule-associated protein tau occurs in an assembled and hyperphosphorylated state in the cytoplasm of neurons and glial cells in Alzheimer's disease (AD), progressive supranuclear palsy, chronic traumatic encep...

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Section: Trim21 Is the Sole Protective Fc Receptor In A Human Neuronamentioning

confidence: 99%

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

McEwan

Falcon

Vaysburd

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

160

163

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“…Moreover, antibodies against these proteins can regulate inflammation and facilitate the clearance of target proteins via autophagy or microglia (Fig. 2) [61][62][63][64][65][66]. Neurodegenerative diseases are associated with signs of chronic neuroinflammation and elevated levels of several Fig.…”

Section: Introductionmentioning

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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“…For a number of years tau was considered to be purely intracellular. Sigurdsson et al reported antibodies inside neurons and proposed that antibody-mediated clearance of intracellular tau aggregates follows the lysosomal pathway [74,75]. Further studies have revealed that tau antibody uptake into neurons correlates well with tau levels.…”

Section: Targeting Taumentioning

confidence: 99%

Opportunities for Conformation-Selective Antibodies in Amyloid-Related Diseases

Westwood

Lawson

2015

Antibodies

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Assembly of misfolded proteins into fibrillar deposits is a common feature of many neurodegenerative diseases. Developing effective therapies to these complex, and not yet fully understood diseases is currently one of the greatest medical challenges facing society. Slow and initially asymptomatic onset of neurodegenerative disorders requires profound understanding of the processes occurring at early stages of the disease including identification and structural characterisation of initial toxic species underlying neurodegeneration. In this review, we chart the latest progress made towards understanding the multifactorial process leading to amyloid formation and highlight efforts made in the development of therapeutic antibodies for the treatment of amyloid-based disorders. The specificity and selectivity of conformational antibodies make them attractive research probes to differentiate between transient states preceding formation of mature fibrils and enable strategies for potential therapeutic intervention to be considered.

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Two Novel Tau Antibodies Targeting the 396/404 Region Are Primarily Taken Up by Neurons and Reduce Tau Protein Pathology

Cited by 149 publications

References 58 publications

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation

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

Opportunities for Conformation-Selective Antibodies in Amyloid-Related Diseases

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