Solanezumab—prospects for meaningful interventions in AD?

Background:Recent studies have implicated specific assembly subtypes of β-amyloid (Aβ) peptide, specifically soluble oligomers (soAβ) as disease-relevant structures that may underlie memory loss in Alzheimer disease. Removing existing soluble and insoluble Aβ assemblies is thought to be essential for any attempt at stabilizing brain function and slowing cognitive decline in Alzheimer disease. IV immunoglobulin (IVIg) therapies have been shown to contain naturally occurring polyclonal antibodies that recognize conformational neoepitopes of soluble or insoluble Aβ assemblies including soAβ. These naturally occurring polyclonal antibodies have been suggested to underlie the apparent clinical benefits of IVIg. However, direct evidence linking anti-Aβ antibodies to the clinical bioactivity of IVIg has been lacking.Methods:Five-month-old female Dutch APP E693Q mice were treated for 3 months with neat IVIg or with IVIg that had been affinity-depleted over immobilized Aβ conformers in 1 of 2 assembly states. Memory was assessed in a battery of tests followed by quantification of brain soAβ levels using standard anti-soAβ antibodies.Results:We provide evidence that NU4-type soAβ (NU4-soAβ) assemblies accumulate in the brains of Dutch APP E693Q mice and are associated with defects in memory, even in the absence of insoluble Aβ plaques. Memory benefits were associated with depletion from APP E693Q mouse brain of NU4-soAβ and A11-soAβ but not OC-type fibrillar Aβ oligomers.Conclusions:We propose that targeting of specific soAβ assembly subtypes may be an important consideration in the therapeutic and/or prophylactic benefit of anti-Aβ antibody drugs.

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“…While prior active or passive immunotherapies have been successful in AD mouse models, success in clinical trials has been elusive. 2 …”

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confidence: 99%

Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes

Knight

Kim

Kottwitz

et al. 2016

Neurol Neuroimmunol Neuroinflamm

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“…Multiple passive vaccinations have progressed to Phase III clinical trials, however none have proved effective in treating the cognitive deficits experienced in AD [ 73 ]. Recently Eli Lilly reported on its vaccine Solaneuzumab, which showed no significant effect on cognition in the overall population it examined for its Phase III trial, but did show some benefits for the younger participants in the study upon post hoc analysis of the data [ 77 ]. The results of the Solaneuzumab trial underscore one of the primary explanations for the failures of both Aβ vaccinations and inhibitors of amyloidogenesis: namely, that these interventions are only effective when given to presymptomatic patients.…”

Section: Current Drug Therapies For Alzheimer’s Diseasementioning

confidence: 99%

The Role of microRNAs in Alzheimer’s Disease and Their Therapeutic Potentials

Shaik

Tamargo

Abubakar

et al. 2018

Genes

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MicroRNAs (miRNAs) are short, endogenous, non-coding RNAs that post-transcriptionally regulate gene expression by base pairing with mRNA targets. Altered miRNA expression profiles have been observed in several diseases, including neurodegeneration. Multiple studies have reported altered expressions of miRNAs in the brains of individuals with Alzheimer’s disease (AD) as compared to those of healthy elderly adults. Some of the miRNAs found to be dysregulated in AD have been reported to correlate with neuropathological changes, including plaque and tangle accumulation, as well as altered expressions of species that are known to be involved in AD pathology. To examine the potentially pathogenic functions of several dysregulated miRNAs in AD, we review the current literature with a focus on the activities of ten miRNAs in biological pathways involved in AD pathogenesis. Comprehensive understandings of the expression profiles and activities of these miRNAs will illuminate their roles as potential therapeutic targets in AD brain and may lead to the discovery of breakthrough treatment strategies for AD.

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“…Also, the passive immunotherapy did not do much better than active immunotherapy. Several antibodies targeting Aβ have failed in clinical trials, including bapineuzumab (Pfizer/Johnson & Johnson) [ 13 , 14 ], Crenezumab (Genentech) [ 15 , 16 ], solanezumab (Eli Lilly) [ 16 – 18 ] and ponezumab (Johnson & Johnson /Pfizer) [ 19 – 21 ]. In addition, although passive immunotherapy could overcome some problems of active immunotherapy, there were still inevitable side effects such as amyloid-related imaging abnormalities [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…A phase Ib trial of aducanumab (Biogen) showed a positive correlation between brain Aβ levels and disease exacerbation as measured by Clinical Dementia Rating [ 29 – 31 ]. Even the failed phase III EXPEDITION3 trial of solanezumab (Eli Lilly) still demonstrated better performance in Clinical Dementia Rating Sum of Boxes and beneficial impacts on Mini-Mental State Examination and Activities of Daily Living [ 17 , 18 , 32 , 33 ]. Thus, despite all kinds of problems, immunotherapy may still be the better approach to modify the extent of neurodegeneration in AD currently [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

Alzheimer’s disease hypothesis and related therapies

Wang

Geng

2018

Transl Neurodegener

469

332

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Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause for dementia. There are many hypotheses about AD, including abnormal deposit of amyloid β (Aβ) protein in the extracellular spaces of neurons, formation of twisted fibers of tau proteins inside neurons, cholinergic neuron damage, inflammation, oxidative stress, etc., and many anti-AD drugs based on these hypotheses have been developed. In this review, we will discuss the existing and emerging hypothesis and related therapies.

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Solanezumab—prospects for meaningful interventions in AD?

Cited by 13 publications

References 10 publications

Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes

Effective anti-Alzheimer Aβ therapy involves depletion of specific Aβ oligomer subtypes

The Role of microRNAs in Alzheimer’s Disease and Their Therapeutic Potentials

Alzheimer’s disease hypothesis and related therapies

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