Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice

Boimel, Moran; Grigoriadis, Nikolaos; Lourbopoulos, Athanasios; Haber, Esther Piltcher; Abramsky, Oded; Rosenmann, Hanna

doi:10.1016/j.expneurol.2010.05.010

Cited by 165 publications

(140 citation statements)

References 40 publications

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“…Both approaches targeted the phosphoserine 396 and 404 region and consistently reduced pathological Tau and ameliorated related functional impairments (10 -12). These findings have been confirmed and extended by other groups as well (13)(14)(15)(16)(17)(18).…”

supporting

confidence: 85%

Antibody Uptake into Neurons Occurs Primarily via Clathrin-dependent Fcγ Receptor Endocytosis and Is a Prerequisite for Acute Tau Protein Clearance

Congdon¹,

Sait

et al. 2013

Journal of Biological Chemistry

178

182

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Background: How Tau immunotherapy clears Tau is not well known. Results: Tau antibody uptake correlates with Tau levels, is primarily via clathrin-dependent Fc␥II/III endocytosis, and is required for acute Tau clearance. Conclusion: Following receptor-mediated uptake into neurons, antibodies co-localize with Tau aggregates and promote Tau clearance. Significance: Results support intracellular clearance as a viable route for immunotherapy and have major implications for future development.

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supporting

confidence: 85%

Antibody Uptake into Neurons Occurs Primarily via Clathrin-dependent Fcγ Receptor Endocytosis and Is a Prerequisite for Acute Tau Protein Clearance

Congdon¹,

Sait

et al. 2013

Journal of Biological Chemistry

178

182

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“…Similar to the amyloid immunotherapy field, tau active immunization provided the first evidence that pathologic spreading could be reduced in long-term efficacy studies [74][75][76][77]. These studies have more recently been followed by passive immunotherapy studies also showing success in reducing pathology and even rescuing motor deficits in tau transgenic mice [78,79].…”

Section: Slowing the Spreading Of Tau Pathology With Anti-tau Antibodiesmentioning

confidence: 99%

Developing Therapeutic Antibodies for Neurodegenerative Disease

Yu¹,

Watts²

2013

Neurotherapeutics

180

171

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The central nervous system has been considered off-limits to antibody therapeutics. However, recent advances in preclinical and clinical drug development suggest that antibodies can cross the blood-brain barrier in limited quantities and act centrally to mediate their effects. In particular, immunotherapy for Alzheimer's disease has shown that targeting beta amyloid with antibodies can reduce pathology in both mouse models and the human brain, with strong evidence supporting a central mechanism of action. These findings have fueled substantial efforts to raise antibodies against other central nervous system targets, particularly neurodegenerative targets, such as tau, beta-secretase, and alpha-synuclein. Nevertheless, it is also apparent that antibody penetration across the blood-brain barrier is limited, with an estimated 0.1-0.2 % of circulating antibodies found in brain at steady-state concentrations. Thus, technologies designed to improve antibody uptake in brain are receiving increased attention and are likely going to represent the future of antibody therapy for neurologic diseases, if proven safe and effective. Herein we review briefly the progress and limitations of traditional antibody drug development for neurodegenerative diseases, with a focus on passive immunotherapy. We also take a more in-depth look at new technologies for improved delivery of antibodies to the brain.

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“…Tau reduction also protects transgenic and non-transgenic mice against excitotoxicity [56]. Immunization strategies targeting tau ameliorates the tau associated pathology, and could be a potential strategy for treatment of AD [87][88][89].…”

Section: Taumentioning

confidence: 99%

Slow Excitotoxicity in Alzheimer's Disease

Ong

Tanaka

Dawe

et al. 2013

JAD

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Abstract. Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations in N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as A␤PP/A␤ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD.

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Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice

Cited by 165 publications

References 40 publications

Antibody Uptake into Neurons Occurs Primarily via Clathrin-dependent Fcγ Receptor Endocytosis and Is a Prerequisite for Acute Tau Protein Clearance

Antibody Uptake into Neurons Occurs Primarily via Clathrin-dependent Fcγ Receptor Endocytosis and Is a Prerequisite for Acute Tau Protein Clearance

Developing Therapeutic Antibodies for Neurodegenerative Disease

Slow Excitotoxicity in Alzheimer's Disease

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