scholarly journals Vaccination with (1–11)E2 in alum efficiently induces an antibody response to β-amyloid without affecting brain β-amyloid load and microglia activation in 3xTg mice

Author(s):  
Francesca Mantile ◽  
Angelo Capasso ◽  
Nadia Villacampa ◽  
Maria Donnini ◽  
Giovanna L. Liguori ◽  
...  

AbstractImmunization against β-amyloid (Aβ) is pursued as a possible strategy for the prevention of Alzheimer’s disease (AD). In clinical trials, Aβ 1–42 proved poorly immunogenic and caused severe adverse effects; therefore, safer and more immunogenic candidate vaccines are needed. Multimeric protein (1–11)E2 is able to induce an antibody response to Aβ, immunological memory, and IL-4 production, with no concomitant anti-Aβ T cell response. Antisera recognize Aβ oligomers, protofibrils, and fibrils. In this study, we evaluated the effect of prophylactic immunization with three doses of (1–11)E2 in alum in the 3xTg mouse model of AD. Immunization with (1–11)E2 efficiently induced anti-Aβ antibodies, but afforded no protection against Aβ accumulation and neuroinflammation. The identification of the features of the anti-Aβ immune response that correlate with the ability to prevent Aβ accumulation remains an open problem that deserves further investigation.

2021 ◽  
Vol 7 (21) ◽  
pp. eabe4601
Author(s):  
Sandro Da Mesquita ◽  
Jasmin Herz ◽  
Morgan Wall ◽  
Taitea Dykstra ◽  
Kalil Alves de Lima ◽  
...  

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.


2014 ◽  
Vol 21 (5) ◽  
pp. 737-746 ◽  
Author(s):  
Christopher D. O'Donnell ◽  
Amber Wright ◽  
Leatrice Vogel ◽  
Kobporn Boonnak ◽  
John J. Treanor ◽  
...  

ABSTRACTThe hypothesis of original antigenic sin (OAS) states that the imprint established by an individual's first influenza virus infection governs the antibody response thereafter. Subsequent influenza virus infection results in an antibody response against the original infecting virus and an impaired immune response against the newer influenza virus. The purpose of our study was to seek evidence of OAS after infection or vaccination with the 2009 pandemic H1N1 (2009 pH1N1) virus in ferrets and humans previously infected with H1N1 viruses with various antigenic distances from the 2009 pH1N1 virus, including viruses from 1935 through 1999. In ferrets, seasonal H1N1 priming did not diminish the antibody response to infection or vaccination with the 2009 pH1N1 virus, nor did it diminish the T-cell response, indicating the absence of OAS in seasonal H1N1 virus-primed ferrets. Analysis of paired samples of human serum taken before and after vaccination with a monovalent inactivated 2009 pH1N1 vaccine showed a significantly greater-fold rise in the titer of antibody against the 2009 pH1N1 virus than against H1N1 viruses that circulated during the childhood of each subject. Thus, prior experience with H1N1 viruses did not result in an impairment of the antibody response against the 2009 pH1N1 vaccine. Our data from ferrets and humans suggest that prior exposure to H1N1 viruses did not impair the immune response against the 2009 pH1N1 virus.


Author(s):  
ARVIND NARWAT ◽  
VIVEK SHARMA ◽  
SUNEEL KUMAR ◽  
SEEMA RANI

The management of Alzheimer's disease (AD) has been a long-standing challenge and area of interest. Advances in knowledge of the pathogenesis of disease and an increase in disease burden have prompted investigation into innovative therapeutics over the last two decades. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target β-amyloid (Aβ) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the 'Aβ hypothesis', there are a number of newer approaches to treat AD. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.


2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Jian-Xiang Zhang ◽  
Yi-Hui Lai ◽  
Pan-Ying Mi ◽  
Xue-Ling Dai ◽  
Ran Zhang ◽  
...  

Abstract Background Brain amyloid deposition is one of the main pathological characteristics of Alzheimer’s disease (AD). Soluble oligomers formed during the process that causes β-amyloid (Aβ) to aggregate into plaques are considered to have major neurotoxicity. Currently, drug development for the treatment of Alzheimer’s disease has encountered serious difficulties. Our newly proposed solution is to accelerate the aggregation of Aβ to reduce the amount of cytotoxic Aβ oligomers in brain tissue. This strategy differs from the existing strategy of reducing the total Aβ content and the number of amyloid plaques. Method In this study, we screened a small library and found that a flavonoid compound (ZGM1) promoted the aggregation of β-amyloid (Aβ). We further verified the binding of ZGM1 to Aβ42 using a microscale thermophoresis (MST) assay. Subsequently, we used dot blotting (DB), transmission electron microscopy (TEM), and thioflavin T fluorescence (ThT) measurements to study the aggregation of Aβ under the influence of ZGM1. By using cell experiments, we determined whether ZGM1 can inhibit the cytotoxicity of Aβ. Finally, we studied the protective effects of ZGM1 on cognitive function in APPswe/PS1 mice via behavioral experiments and measured the number of plaques in the mouse brain by thioflavin staining. Results ZGM1 can bind with Aβ directly and mediate a new Aβ assembly process to form reticular aggregates and reduce the amount of Aβ oligomers. Animal experiments showed that ZGM1 can significantly improve cognitive dysfunction and that Aβ plaque deposition in the brain tissue of mice in the drug-administered group was significantly increased. Conclusion Our research suggests that promoting Aβ aggregation is a promising treatment method for AD and deserves further investigation.


2013 ◽  
Vol 288 (23) ◽  
pp. 16937-16948 ◽  
Author(s):  
Wayne W. Poon ◽  
Anthony J. Carlos ◽  
Brittany L. Aguilar ◽  
Nicole C. Berchtold ◽  
Crystal K. Kawano ◽  
...  

We previously found that BDNF-dependent retrograde trafficking is impaired in AD transgenic mouse neurons. Utilizing a novel microfluidic culture chamber, we demonstrate that Aβ oligomers compromise BDNF-mediated retrograde transport by impairing endosomal vesicle velocities, resulting in impaired downstream signaling driven by BDNF/TrkB, including ERK5 activation, and CREB-dependent gene regulation. Our data suggest that a key mechanism mediating the deficit involves ubiquitin C-terminal hydrolase L1 (UCH-L1), a deubiquitinating enzyme that functions to regulate cellular ubiquitin. Aβ-induced deficits in BDNF trafficking and signaling are mimicked by LDN (an inhibitor of UCH-L1) and can be reversed by increasing cellular UCH-L1 levels, demonstrated here using a transducible TAT-UCH-L1 strategy. Finally, our data reveal that UCH-L1 mRNA levels are decreased in the hippocampi of AD brains. Taken together, our data implicate that UCH-L1 is important for regulating neurotrophin receptor sorting to signaling endosomes and supporting retrograde transport. Further, our results support the idea that in AD, Aβ may down-regulate UCH-L1 in the AD brain, which in turn impairs BDNF/TrkB-mediated retrograde signaling, compromising synaptic plasticity and neuronal survival.


Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 185-191 ◽  
Author(s):  
Davor Brinc ◽  
Alan H. Lazarus

Abstract Anti-D is routinely and effectively used to prevent hemolytic disease of the fetus and newborn (HDFN) caused by the antibody response to the D antigen on fetal RBCs. Anti-D is a polyclonal IgG product purified from the plasma of D-alloimmunized individuals. The mechanism of anti-D has not been fully elucidated. Antigenic epitopes are not fully masked by anti-D and are available for immune system recognition. However, a correlation has frequently been observed between anti-D-mediated RBC clearance and prevention of the antibody response, suggesting that anti-D may be able to destroy RBCs without triggering the adaptive immune response. Anti-D-opsonized RBCs may also elicit inhibitory FcγRIIB signaling in B cells and prevent B cell activation. The ability of antigen-specific IgG to inhibit antibody responses has also been observed in a variety of animal models immunized with a vast array of different antigens, such as sheep RBCs (SRBC). This effect has been referred to as antibody-mediated immune suppression (AMIS). In animal models, IgG inhibits the antibody response, but the T-cell response and memory may still be intact. IgG does not mask all epitopes, and IgG-mediated RBC clearance or FcγRIIB-mediated B-cell inhibition do not appear to mediate the AMIS effect. Instead, IgG appears to selectively disrupt B cell priming, although the exact mechanism remains obscure. While the applicability of animal models of AMIS to understanding the true mechanism of anti-D remains uncertain, the models have nevertheless provided us with insights into the possible IgG effects on the immune response.


CNS Spectrums ◽  
2008 ◽  
Vol 13 (S16) ◽  
pp. 39-41 ◽  
Author(s):  
Norman R. Relkin

There are currently over two dozen agents targeting β-amyloid (Aβ) in human clinical trials. More than a dozen of these are forms of anti-amyloid immunotherapy. Although other anti-amyloid interventions are further along in the development process, thus far only immunotherapy has provided post-mortem evidence that it can alter elements of the underlying pathology of Alzheimer’s disease (AD) in actual patients.In the past 30 years, there have been many attempts to develop treatments for AD. Early therapies were developed based on a limited understanding of the disease (Slide 1). Prior to the 1980s, a clear pathophysiologic mechanism for AD was not known; instead, symptomatic therapies targeted associated symptoms, such as agitation, insomnia, and psychosis. In the 1970s, several preclinical studies pointed toward synaptic transmission abnormalities, particularly neurochemical abnormalities, as the root cause of AD, and treatments with cholinesterase inhibitors grew out of that theory. Today, the cholinergic hypothesis has been largely discredited in the primary pathogenesis of AD. Another theory based on neurotransmitter abnormalities, the glutaminergic hypothesis, has also gone out of favor as a causal explanation for AD. This did not stop medications based on these mechanisms from finding a meaningful place in the clinical pharmacopeia for treatment of AD.In the 1990s, many clinical trials followed up on epidemiologic studies suggesting systemic causes of AD. These clinical trials focused on anti-inflammatories, hormone replacement, and antioxidants. The trials performed have largely failed, with the possible exception of the trials of vitamin E, an antioxidant. None of these agents have proven useful as disease-modifying therapies for symptomatic AD.


2018 ◽  
Vol 20 (10) ◽  
pp. 6817-6829 ◽  
Author(s):  
Ning Xiang ◽  
Yuan Lyu ◽  
Xiao Zhu ◽  
Ganesan Narsimhan

The mechanism of pore formation in model neural cell membranes by β amyloid (Aβ) peptides was investigated using molecular dynamics simulation which indicated that Aβ oligomers of size equal or greater than 3 has a higher tendency for pore formation than monomers and that cholesterol tends to retard Aβ binding and insertion into the membrane.


2020 ◽  
Author(s):  
Yasmin Khajenoori ◽  
Ayesha Aslam-Mir ◽  
Arezo Ahmadi ◽  
Risa Iwazaki ◽  
Shiv Puliady

The SARS-CoV-2 outbreak of winter 2019 and 2020 has boomed into a global pandemic of a highly contagious respiratory illness, COVID-19. This affliction causes severe acute respiratory distress and, for many with pre-existing conditions, can threaten to be fatal. Many pharmaceutical manufacturers have been allowed to accelerate their vaccination development, an otherwise lengthy and several stage process. Vaccines being developed are both novel and traditional; some target the spike protein, an agent in SARS-CoV-2 contagion, as recent studies showed that it produced polyclonal antibody responses and neutralized SARS-CoV-2 S-mediated entry, as well as the receptor binding domain. Animal testing used pre-clinical trial in Sinovac’s PiCoVacc show promise to create SARS-CoV-2–specific antibody responses targeting S-specific and RBD-specific IgG in mice, which is why PiCoVacc was shown to mitigate the severity of the virus’s symptoms in all rhesus macaques tested. Additionally, testing of Novavax’s NVX-CoV2373 used live mice and baboon models and has shown promising results of high affinity antibody responses targeting SARS-CoV-215. In this pre-clinical trial, the spleens of animal models who received NVX-CoV2373 followed by a Matrix-M adjuvant, or an immune response boosting agent, showed increased frequencies of TFH cells and GC B cells, encouraging Novavax to continue into clinical trial stages15. Vaccine candidates have already produced post-clinical trial results. INO-4800, a DNA vaccine made by INOVIO, has passed phase 1 clinical trials, while demonstrating general safety in all volunteers and generating immunological response rates and T cell immune responses in 94% of the participants. Moderna and Pfizer show promise with mRNA vaccines, both for the spike protein and receptor domain12; these follow a novel approach and have currently moved into their phase two trials due to increased immune response and reduced adverse effects initially in clinic; Moderna’s spike protein vaccine showed titers of antibody 2.1 times higher than those convalescent with the 100ug dosage, in addition to elevated T-cell response post inoculation for all tested doses.3, 9 Another vaccine, known as ChAdOx1 nCoV-19, a chimpanzee adenovirus-vectored vaccine, has been tested on 1077 healthy adults through single and double doses. The results have shown that the single dose elicited both humoral and cellular responses against SARS-CoV-2, with a booster immunization augmenting antibody titers. Within the ChAdOx1 nCoV-19 groups, local and systemic reactions were more common5. Patients were randomly assigned single intramuscular injections of ChAdOx1 nCoV-19 at doses of 5 × 1010 viral particles or MenACWY5. After the vaccination procedure, participants were observed in the clinic for 30-50 minutes and asked to take note of any abnormal events during the 28-day follow up period5. Evaluating the adenovirus, mRNA, DNA, inactivated, and subunit vaccines currently in accelerated development by pharmaceutical manufacturers will allow for a comprehensive review of which vaccine is most ready for widespread use and can successfully and safely curtail further spread of SARS-CoV-2.


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