Alzheimer&amp;rsquo;s disease and immunotherapy: what is wrong with clinical trials?

Kohyama, Kuniko; Matsumoto, Yoh

doi:10.2147/itt.s49923

Cited by 12 publications

(12 citation statements)

References 40 publications

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“…Until now, preclinical assessment of candidate antibodies has relied largely on in vitro binding experiments with synthetic Aβ 25 , 38 , 59 and passive immunization of APP transgenic mice 60 – 62 . However, these approaches have not translated well to humans 2 – 4 , and it is uncertain whether synthetic Aβ peptides or APP transgenic mice can yield the type of neurotoxic Aβ assemblies that accumulate in the brains of humans with AD. In regard to behavioral deficits observed in some APP transgenic mice, it is unclear whether these are due to Aβ and/or a result of over-expression of APP 63 .…”

Section: Discussionmentioning

confidence: 99%

“…Despite generally good outcomes in preclinical mouse models, anti-Aβ immunotherapy has yielded limited success in humans 2 , 3 . Explanations offered to account for the poor translation of pre-clinical lead antibodies into human therapies include imperfect trial design, intervention at a disease stage when there is already significant neural loss, and inappropriate target selectivity of the antibodies used 2 , 4 , 5 .…”

Section: Introductionmentioning

confidence: 99%

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An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease

et al. 2018

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Although the amyloid β-protein (Aβ) is believed to play an initiating role in Alzheimer’s disease (AD), the molecular characteristics of the key pathogenic Aβ forms are not well understood. As a result, it has proved difficult to identify optimal agents that target disease-relevant forms of Aβ. Here, we combined the use of Aβ-rich aqueous extracts of brain samples from AD patients as a source of human Aβ and live-cell imaging of iPSC-derived human neurons to develop a bioassay capable of quantifying the relative protective effects of multiple anti-Aβ antibodies. We report the characterization of 1C22, an aggregate-preferring murine anti-Aβ antibody, which better protects against forms of Aβ oligomers that are toxic to neurites than do the murine precursors of the clinical immunotherapeutics, bapineuzumab and solanezumab. These results suggest further examination of 1C22 is warranted, and that this bioassay maybe useful as a primary screen to identify yet more potent anti-Aβ therapeutics.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease

et al. 2018

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“…Improvement in cognitive potential and the blockage of the aggregation of Aβ peptides was observed when Aβ peptides were administered to AD transgenic mouse models [ 72 ]. In the phase 2 clinical trials of AN1792 (the first active immunotherapeutic agent), about 6% of patients suffered from cellular meningoencephalitis [ 73 , 74 ]. Therefore, there was a need for an alternative to target Aβ plaques and hinder their development without the generation of an immune response [ 2 ].…”

Section: Therapeutic Agents Targeting Amyloid Cascade Eventsmentioning

confidence: 99%

Exploring the Potential of Therapeutic Agents Targeted towards Mitigating the Events Associated with Amyloid-β Cascade in Alzheimer’s Disease

Behl

Kaur

Frățilă

et al. 2020

IJMS

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One of the most commonly occurring neurodegenerative disorders, Alzheimer’s disease (AD), encompasses the loss of cognitive and memory potential, impaired learning, dementia and behavioral defects, and has been prevalent since the 1900s. The accelerating occurrence of AD is expected to reach 65.7 million by 2030. The disease results in neural atrophy and disrupted inter-neuronal connections. Amongst multiple AD pathogenesis hypotheses, the amyloid beta (Aβ) cascade is the most relevant and accepted form of the hypothesis, which suggests that Aβ monomers are formed as a result of the cleavage of amyloid precursor protein (APP), followed by the conversion of these monomers to toxic oligomers, which in turn develop β-sheets, fibrils and plaques. The review targets the events in the amyloid hypothesis and elaborates suitable therapeutic agents that function by hindering the steps of plaque formation and lowering Aβ levels in the brain. The authors discuss treatment possibilities, including the inhibition of β- and γ-secretase-mediated enzymatic cleavage of APP, the immune response generating active immunotherapy and passive immunotherapeutic approaches targeting monoclonal antibodies towards Aβ aggregates, the removal of amyloid aggregates by the activation of enzymatic pathways or the regulation of Aβ circulation, glucagon-like peptide-1 (GLP-1)-mediated curbed accumulation and the neurotoxic potential of Aβ aggregates, bapineuzumab-mediated vascular permeability alterations, statin-mediated Aβ peptide degradation, the potential role of ibuprofen and the significance of natural drugs and dyes in hindering the amyloid cascade events. Thus, the authors aim to highlight the treatment perspective, targeting the amyloid hypothesis, while simultaneously emphasizing the need to conduct further investigations, in order to provide an opportunity to neurologists to develop novel and reliable treatment therapies for the retardation of AD progression.

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“…Although evidence shows that the anomalous protein amyloid beta (Aβ), which exceedingly accumulates in the hippocampus and other cerebral areas of the Alzheimer’s brain, plays a pivotal role in the pathogenesis of the disease [3, 4], outcomes of Aβ-based clinical trials have been, so far, deluding [5].…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of curtailing immune susceptibility in an Alzheimer’s disease model

Benedetto

Burgaletto

Carta

et al. 2019

J Neuroinflammation

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Background Currently, there are no effective therapeutic options for Alzheimer’s disease, the most common, multifactorial form of dementia, characterized by anomalous amyloid accumulation in the brain. Growing evidence points to neuroinflammation as a major promoter of AD. We have previously shown that the proinflammatory cytokine TNFSF10 fuels AD neuroinflammation, and that its immunoneutralization results in improved cognition in the 3xTg-AD mouse. Methods Here, we hypothesize that inflammatory hallmarks of AD might parallel with central and peripheral immune response dysfunction. To verify such hypothesis, we used a triple transgenic mouse model of AD. 3xTg-AD mice were treated for 12 months with an anti-TNFSF10 antibody, and thereafter immune/inflammatory markers including COX2, iNOS, IL-1β and TNF-α, CD3, GITR, and FoxP3 (markers of regulatory T cells) were measured in the spleen as well as in the hippocampus. Results Spleens displayed accumulation of amyloid-β 1–42 (Aβ 1-42 ), as well as high expression of Treg cell markers FoxP3 and GITR, in parallel with the increased levels of inflammatory markers COX2, iNOS, IL-1β and TNF-α, and blunted IL-10 expression. Moreover, CD3 expression was increased in the hippocampus, consistently with FoxP3 and GITR. After chronic treatment of 3xTg-AD mice with an anti-TNFSF10 antibody, splenic FoxP3, GITR, and the above-mentioned inflammatory markers expression was restored to basal levels, while expression of IL-10 was increased. A similar picture was observed in the hippocampus. Such improvement of peripheral and CNS inflammatory/immune response was associated with decreased microglial activity in terms of TNFα production, as well as decreased expression of both amyloid and phosphorylated tau protein in the hippocampus of treated 3xTg-AD mice. Interestingly, we also reported an increased expression of both CD3 and FoxP3, in sections from human AD brain. Conclusions We suggest that neuroinflammation in the brain of 3xTg-AD mice triggered by TNFSF10 might result in a more general overshooting of the immune response. Treatment with an anti-TNFSF10 antibody blunted inflammatory processes both in the spleen and hippocampus. These data confirm the detrimental role of TNFSF10 in neurodegeneration, and corroborate the hypothesis of the anti-TNFSF10 strategy as a potential treatment to improve outcomes in AD. Electronic supplementary material The online version of this article (10.1186/s12974-019-1554-9) contains supplementary material, which is available to authorized users.

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Alzheimer’s disease and immunotherapy: what is wrong with clinical trials?

Cited by 12 publications

References 40 publications

An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease

An in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease

Exploring the Potential of Therapeutic Agents Targeted towards Mitigating the Events Associated with Amyloid-β Cascade in Alzheimer’s Disease

Beneficial effects of curtailing immune susceptibility in an Alzheimer’s disease model

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