Tau Immunotherapy

Sigurdsson, Einar M.

doi:10.1159/000440842

Cited by 54 publications

(40 citation statements)

References 30 publications

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“…Thus, targeting tau pathology could be clinically more efficacious than Aβ-directed clearance therapy for patients with AD. Indeed, active and passive immunotherapies targeting pathological tau have been tested in several transgenic mouse models of AD using different phospho-tau peptides and antibodies, and they have shown great potential [15]. Active immunization with tau phosphopeptides reduces tau pathology [16–22] and rescues or slows cognitive decline in rodents [16, 19, 21, 22].…”

Section: Introductionmentioning

confidence: 99%

Tau passive immunization inhibits not only tau but also Aβ pathology

et al. 2017

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BackgroundAccumulation of hyperphosphorylated tau protein is a histopathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Currently, there is no effective treatment available for these progressive neurodegenerative diseases. In recent years, tau immunotherapy has shown great potential in animal models. We report the effect of immunization with tau antibodies 43D against tau 6–18 and 77E9 against tau 184–195 on tau and amyloid-β (Aβ) pathologies and cognition in triple-transgenic (3×Tg)-AD mice at mild to moderate stages of the disease.MethodsWe immunized 12-month-old female 3×Tg-AD mice with two to six or seven intravenous weekly doses of 15 μg of mouse monoclonal antibody 43D, 77E9, a combination of one-half dose each of 43D and 77E9, or as control of mouse immunoglobulin G (IgG). Age-matched wild-type mice treated with mouse IgG or a mixture of 43D and 77E9 were also used as controls. The effect of immunization with tau antibodies on tau and Aβ pathologies was assessed by Western blot and immunofluorescence analysis, and the effect on cognition was analyzed by using Morris water maze, one-trial novel object recognition, and novel object location tasks.ResultsWe found that two doses of 43D and 77E9 reduced total tau but had no significant impact on hyperphosphorylation of tau. However, six doses of 43D reduced levels of both total tau and tau hyperphosphorylated at Ser262/356 and Ser396/404 sites in the hippocampus. Importantly, both 43D and 77E9 antibodies rescued spatial memory and short-term memory impairments in 3×Tg-AD mice. The beneficial effect of 43D and 77E9 antibodies on cognitive performance was sustained up to 3 months after the last dose. Six doses of immunization with 43D also decreased amyloid precursor protein (APP) level in CA1 and amyloid plaques in subiculum, and showed a trend toward reducing Aβ40 and Aβ42 in the forebrain. Immunization with 43D increased levels of complement components C1 and C9 and resulted in activation of microglia, especially surrounding Aβ plaques.ConclusionsThese findings suggest the potential of passive immunization targeting proximal N-terminal domain tau 6–18 as a disease-modifying approach to AD and related tauopathies.

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Section: Introductionmentioning

confidence: 99%

Tau passive immunization inhibits not only tau but also Aβ pathology

et al. 2017

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“…Others later reported no obvious side effect of mouse immunizations with full-length recombinant tau using a milder adjuvant [37]. We have previously mentioned in reviews our then unpublished observations of enhanced mortality in 3xTg mice and in wild-type mice of the same mixed strain background [51,78], which has now been detailed in a publication [15]. Briefly, this particular mixed strain background led to a strong antibody response to Tau379–408[P-Ser396, 404], and substantial mortality after the fifth immunization.…”

Section: Toxicity Concernsmentioning

confidence: 99%

“…These studies have been confirmed and extended by various groups showing benefits of immune-targeting the pS396/404 tau epitope [2,4,6–9,12,20–27], and other tau epitopes [20,23–25,27–49], which as mentioned above has resulted in eight clinical trials (for a recent review of these trials see [50]), with several more likely to be initiated in the near future. We have highlighted many of these studies in some details in various reviews over the years as they have been reported so it is not necessary to elaborate further on those particular aspects (see for example [51–53]). Instead, I will go over some key points to consider as the field of tau immunotherapy matures.…”

Section: Introductionmentioning

confidence: 99%

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

Sigurdsson

2018

JAD

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Tau immunotherapies have now advanced from proof-of-concept studies to Phase 2 clinical trials. This review briefly outlines developments in the field and discusses how these therapies may work, which involves multiple variables that are connected in complex ways. These various factors are likely to define therapeutic success in humans and have not been thoroughly investigated, at least based on published reports.

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“…Tau immunotherapy has also been explored as a possible means for inhibiting disease progression in AD 45 . Given problems with vaccines, Aβ passive immunotherapy is currently the most popular approach for developing disease-modifying drugs for the treatment of AD 42, 46 .…”

Section: Alzheimer’s Diseasementioning

confidence: 99%

New drugs in psychiatry: focus on new pharmacological targets

et al. 2017

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The approval of psychotropic drugs with novel mechanisms of action has been rare in recent years. To address this issue, further analysis of the pathophysiology of neuropsychiatric disorders is essential for identifying new pharmacological targets for psychotropic medications. In this report, we detail drug candidates being examined as treatments for psychiatric disorders. Particular emphasis is placed on agents with novel mechanisms of action that are being tested as therapies for depression, schizophrenia, or Alzheimer’s disease. All of the compounds considered were recently approved for human use or are in advanced clinical trials. Drugs included here are new antipsychotic medications endowed with a preferential affinity at dopamine D3 receptor (cariprazine) or at glutamatergic or cannabinoid receptors, as well as vortioxetine, a drug approved for managing the cognitive deficits associated with major depression. New mechanistic approaches for the treatment of depression include intravenous ketamine or esketamine or intranasal esketamine. As for Alzheimer’s disease, the possible value of passive immunotherapy with agents such as aducanumab is considered to be a potential disease-modifying approach that could slow or halt the progressive decline associated with this devastating disorder.

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Tau Immunotherapy

Cited by 54 publications

References 30 publications

Tau passive immunization inhibits not only tau but also Aβ pathology

Tau passive immunization inhibits not only tau but also Aβ pathology

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

New drugs in psychiatry: focus on new pharmacological targets

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