Passive Aβ Immunotherapy: Current Achievements and Future Perspectives

Schilling, Stephan; Rahfeld, Jens‐Ulrich; Lues, Inge; Lemere, Cynthia A.

doi:10.3390/molecules23051068

Cited by 46 publications

(53 citation statements)

References 103 publications

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“…β-Amyloid peptides are potent inducers of innate immune responses via different pattern recognition receptors [104]. Nonetheless, randomized clinical trials with nonsteroidal anti-inflammatory drugs (NSAID) as well as the amyloid-based immunotherapies have been unable to prevent the pathogenesis of AD [105,106]. Inflammasomes are activated in the AD pathology which might generate an inflammatory microenvironment in the AD brain [107,108].…”

Section: Chronic Inflammation Is a Hallmark Of Aging Process And Alzhmentioning

confidence: 99%

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

2020

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The endoplasmic reticulum (ER) contains stress sensors which recognize the accumulation of unfolded proteins within the lumen of ER, and subsequently these transducers stimulate the unfolded protein response (UPR). The ER sensors include the IRE1, PERK, and ATF6 transducers which activate the UPR in an attempt to restore the quality of protein folding and thus maintain cellular homeostasis. If there is excessive stress, UPR signaling generates alarmins, e.g., chemokines and cytokines, which activate not only tissue-resident immune cells but also recruit myeloid and lymphoid cells into the affected tissues. ER stress is a crucial inducer of inflammation in many pathological conditions. A chronic low-grade inflammation and cellular senescence have been associated with the aging process and many age-related diseases, such as Alzheimer's disease. Currently, it is known that immune cells can exhibit great plasticity, i.e., they are able to display both pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner. The microenvironment encountered in chronic inflammatory conditions triggers a compensatory immunosuppression which defends tissues from excessive inflammation. Recent studies have revealed that chronic ER stress augments the suppressive phenotypes of immune cells, e.g., in tumors and other inflammatory disorders. The activation of immunosuppressive network, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), has been involved in the aging process and Alzheimer's disease. We will examine in detail whether the ER stress-related changes found in aging tissues and Alzheimer's disease are associated with the activation of immunosuppressive network, as has been observed in tumors and many chronic inflammatory diseases.

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Section: Chronic Inflammation Is a Hallmark Of Aging Process And Alzhmentioning

confidence: 99%

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

2020

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“…55 As the treatment of APP transgenic mouse models of AD with therapeutic antibodies to Aβ showed significant reduction in the level of brain Aβ and reversed the memory deficits observed in the object recognition task and Morris water maze, passive immunization has been tested in clinical trials for treatment of AD using the following antibodies: bapineuzumab, AAB-003, GSK933776, solanezumab, ponezumab, BAN2401, gantenerumab, aducanumab, LY3002813, crenezumab, SAR228810, and MEDI1814. 29,56 They target different epitopes of Aβ and show different preferences for binding Aβ monomer, oligomer, or fibrils (Figure 1). 56,57 They also belong to different IgG classes, which stimulate different types of immune responses.…”

Section: Vaccination For Admentioning

confidence: 99%

Rationale for the development of an Alzheimer’s disease vaccine

Kwan

Konno

Chan

et al. 2019

Human Vaccines & Immunotherapeutics

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Vaccination traditionally has targeted infectious agents and thus has not heretofore been used to prevent neurodegenerative illness. However, amyloid β (Aβ) or tau, which can act like infectious proteins, or prions, might induce Alzheimer's disease (AD). Furthermore, evidence suggests that traditional infectious agents, including certain viruses and bacteria, may trigger AD. It is therefore worth exploring whether removing such targets could prevent AD. Although failing to treat AD patients who already display cognitive impairment, Aβ monoclonal antibodies are being tested in pre-symptomatic, at-risk individuals to prevent dementia. These antibodies might become the first AD therapeutics. However, their high cost will keep them out of the arms of the vast majority of patients, who increasingly live in developing countries. Because vaccines produce antibodies internally at much lower cost, vaccination might be the most promising approach to reducing the global burden of dementia.

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“…Antibodies directed against Aβ represent another class of therapeutic molecules under consideration for the treatment of AD (Schilling, Rahfeld, Lues, & Lemere, 2018). Pre-incubation with the 6E10 anti-Aβ antibody, shown to significantly improve cognitive performance in mouse and rat models of AD (Wang et al, 2016), effectively reduced Aβ binding to α7nAChRs (Figure 3e).…”

Section: Effect Of Well-characterized Compounds On the Aβ/α7nachr Imentioning

confidence: 99%

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

Cecon

Dam

Luka

et al. 2019

British J Pharmacology

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Background and Purpose Progressive dysfunction of cholinergic transmission is a well‐known characteristic of Alzheimer's disease (AD). Amyloid β (Aβ) peptide oligomers are known to play a central role in AD and are suggested to impair the function of the cholinergic nicotinic ACh receptor α7 (α7nAChR). However, the mechanism underlying the effect of Aβ on α7nAChR function is not fully understood, limiting the therapeutic exploration of this observation in AD. Here, we aimed to detect and characterize Aβ binding to α7nAChR, including the possibility of interfering with this interaction for therapeutic purposes. Experimental Approach We developed a specific and quantitative time‐resolved FRET (TR‐FRET)‐based binding assay for Aβ to α7nAChR and pharmacologically characterized this interaction. Key Results We demonstrated specific and high‐affinity (low nanomolar) binding of Aβ to the orthosteric binding site of α7nAChR. Aβ binding was prevented and reversed by the well‐characterized orthosteric ligands of α7nAChR (epibatidine, α‐bungarotoxin, methylylcaconitine, PNU‐282987, S24795, and EVP6124) and by the type II positive allosteric modulator (PAM) PNU‐120596 but not by the type I PAM NS1738. Conclusions and Implications Our TR‐FRET Aβ binding assay demonstrates for the first time the specific binding of Aβ to α7nAChR, which will be a crucial tool for the development, testing, and selection of a novel generation of AD drug candidates targeting Aβ/α7nAChR complexes with high specificity and fewer side effects compared to currently approved α7nAChR drugs. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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Passive Aβ Immunotherapy: Current Achievements and Future Perspectives

Cited by 46 publications

References 103 publications

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

ER stress activates immunosuppressive network: implications for aging and Alzheimer’s disease

Rationale for the development of an Alzheimer’s disease vaccine

Quantitative assessment of oligomeric amyloid β peptide binding to α7 nicotinic receptor

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