Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

Sigurdsson, Einar M.

doi:10.3233/jad-179937

Cited by 52 publications

(21 citation statements)

References 78 publications

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“…Meanwhile, tau-based immunotherapies are currently in early stages of clinical development. RG7345, which is a humanized monoclonal antibody targeting the tau phosphoepitope pS422, caused an improvement in a transgenic mouse AD model but was discontinued after Phase I clinical trials (Collin et al 2014;Sigurdsson 2018). Besides these approaches, drug candidates that target different neuronal receptors (e.g.…”

Section: Current Treatment Optionsmentioning

confidence: 99%

The Promises and Challenges of Erythropoietin for Treatment of Alzheimer’s Disease

et al. 2019

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Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, and intracellular neurofibrillary tangles and extracellular amyloid-beta protein deposits represent the major pathological hallmarks of the disease. Currently available treatments provide some symptomatic relief but fail to modify primary pathological processes that underlie the disease. Erythropoietin (EPO), a hematopoietic growth factor, acts primarily to stimulate erythroid cell production, and is clinically used to treat anemia. EPO has evolved as a therapeutic agent for neurodegeneration and has improved neurological outcomes and AD pathology in rodents. However, penetration of the blood-brain barrier (BBB) and negative hematopoietic effects are the two major challenges for the therapeutic development of EPO for chronic neurodegenerative diseases like AD. The transferrin receptors at the BBB, which are responsible for transporting transferrin-bound iron from the blood into the brain parenchyma, can be used to shuttle therapeutic molecules across the BBB. In this review, we discuss the role of EPO as a potential neurotherapeutic for AD, challenges associated with EPO development for AD, and targeting the BBB transferrin receptor for EPO brain delivery.

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Section: Current Treatment Optionsmentioning

confidence: 99%

The Promises and Challenges of Erythropoietin for Treatment of Alzheimer’s Disease

et al. 2019

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“…Tau accumulation is perhaps the most prominent feature of CTE and thus represents the most intuitive target for antibody therapeutic intervention. Given phosphorylated tau's strong intraneuronal localization in CTE, one could reason that an intracellular-acting antibody may be more potent in combating tauopathy (Sigurdsson, 2018). However, intracellular translocation of mAbs is challenging and highly dependent on receptor affinity and charge (Sigurdsson, 2018;Katsinelos et al, 2019).…”

Section: Immunotherapymentioning

confidence: 99%

“…Given phosphorylated tau's strong intraneuronal localization in CTE, one could reason that an intracellular-acting antibody may be more potent in combating tauopathy (Sigurdsson, 2018). However, intracellular translocation of mAbs is challenging and highly dependent on receptor affinity and charge (Sigurdsson, 2018;Katsinelos et al, 2019). Studies have suggested that tau pathology occurs through extracellular mechanisms (Le et al, 2012;Walker et al, 2013); thus, an antibody that acts extracellularly or merely blocks neuronal p-tau import (Nobuhara et al, 2017) may be a feasible alternative.…”

Section: Immunotherapymentioning

confidence: 99%

“…Given that most pathological tau is intracellularly localized, human chimerization of tau antibodies has been shown to alter charge and binding ultimately reducing efficiency (Congdon et al, 2019). While no clinical trials exist specifically for CTE, there are at least half a dozen clinical trials exploring the therapeutic effects of various tau antibodies on patients affected by AD (Sigurdsson, 2018), any of which may address the tauopathy of CTE if they showed success in AD.…”

Section: Immunotherapymentioning

confidence: 99%

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Recent Preclinical Insights Into the Treatment of Chronic Traumatic Encephalopathy

Breen

Krishnan

2020

Front. Neurosci.

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Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with significant mortality and morbidity. The central pathophysiological mechanisms by which repetitive cranial injury results in the neurodegeneration of CTE are poorly understood. Current well-established working models emphasize a central role for trauma-induced excessive phosphorylation and accumulation of insoluble tangles of Tau protein. In this review, we summarize recent data from preclinical animal models of CTE where a series of candidate treatments have been carefully evaluated, including kinase inhibitors, antibody therapy, and anti-inflammatory therapies. We discuss the overall translational potential of these approaches and provide recommendations for future bench-to-bedside treatment strategies.

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“…There are currently no disease-modifying treatments available for these diseases, and therefore it is desirable to design strategies that could directly target the aggregation of these proteins or modulate their ability to propagate from one brain region to another. Ongoing clinical trials with immunotherapy are focused on clearing the aggregates when they are in the extracellular space, and can be viewed as a strategy to limit prion-like spreading of the pathology (Gallardo and Holtzman, 2017;Sigurdsson, 2018;Panza et al, 2019).…”

mentioning

confidence: 99%

Editorial: Protein Misfolding and Spreading Pathology in Neurodegenerative Diseases

Lázaro

Bellucci

Brundin

et al. 2020

Front. Mol. Neurosci.

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Editorial on the Research Topic Protein Misfolding and Spreading Pathology in Neurodegenerative Diseases A common pathological hallmark among different neurodegenerative diseases is the accumulation of aggregated proteins that might cause cellular dysfunction and, eventually, lead to cell death. Amyloid-beta, Tau, alpha-synuclein, TDP-43, or the prion protein, are just a few examples of proteins that can aggregate and contribute to the pathogenesis of neurodegenerative diseases with diverse clinical manifestations (Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, Parkinson's disease, Lewy body dementia, multiple system atrophy, amyotrophic lateral sclerosis among the most common). Emerging evidence suggests that the progression of symptoms in patients affected by such disorders correlates with the spreading of pathology through the brain, but the molecular mechanisms underlying aggregation and propagation of protein aggregates are still obscure. This Research Topic focuses on the structural and molecular characteristics of aggregation-prone proteins and resumes new aspects of pathology spreading. A series of 10 articles provides an exciting up-to-date overview of core biological features of prion and prion-like neurodegenerative disorders. Protein aggregation is a common feature among numerous neurodegenerative diseases, and is thought to culminate with detrimental effects for the cells where the proteins accumulate. Despite the commonalities of protein aggregation and cell dysfunction, the pathobiological bases of these diseases may differ. For example, the two characteristic protein deposits in Alzheimer's disease (AD) are the extracellular senile plaques, whose main constituent are amyloid-β (Aβ) fibrils, and intraneuronal neurofibrillary tangles (NFT), composed of hyperphosphorylated Tau protein (

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Tau Immunotherapies for Alzheimer’s Disease and Related Tauopathies: Progress and Potential Pitfalls1

Cited by 52 publications

References 78 publications

The Promises and Challenges of Erythropoietin for Treatment of Alzheimer’s Disease

The Promises and Challenges of Erythropoietin for Treatment of Alzheimer’s Disease

Recent Preclinical Insights Into the Treatment of Chronic Traumatic Encephalopathy

Editorial: Protein Misfolding and Spreading Pathology in Neurodegenerative Diseases

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