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Principal Investigator: Arya Biragyn
Organization: NATIONAL INSTITUTE ON AGING
Fiscal Year: 2023
Award: $447,017
Funding agency: National Institute on Aging
The role of aging-linked immune dysregulation in dementia and Alzheimers disease (AD) remains poorly understood. Recently we proposed that AD requires B cells. We demonstrated that AD cannot progress if B cells are lost (Kim et al., Nature Commun., 2021). Thus, in addition to the benefit (as producers of antibody that reduces amyloid burden), B cells can also be pathogenic in AD. Our preliminary results indicate that the AD B cells resemble 4BL cells, potentially pathogenic B1 B cells, activated B cells we discovered in elderly hosts (Lee-Chang et al., Blood, 2014; J. Immunol., 2016). They promote insulin resistance in aging (Bodogai et al., Science Translational. Med, 2018). Although our previous results demonstrated importance of Abeta-specific antibody in protection from cognitive impairments caused by amyloid burden in AD and Down syndrome (DS) (Olkhanud et al., Vaccine 2013; Illouz et al., Vaccine, 2021; Illouz et al., Vaccine, 2021; Communic. Biol, 2021), our recent results suggest that the immunoglobulin (or even beta-specific antibody) may also participate in the AD manifestation. We evaluated immunoglobulin (Ig) in the brain of mice with AD using immunofluorescent staining. Compared with age/sex-matched mice, brain of AD mice was significantly increased in Ig. This Ig was mostly associated with Abeta plaques and microglia. Importantly, depletion of circulating B cells with anti-CD20/B220 antibody markedly decreased Ig in the brain and reversed AD symptoms in mice with AD. Thus, corroborating our hypothesis that the brain Ig may also facilitate AD, presumably via exacerbating brain inflammation. Since effector function of Ig depends on its isotype, we are testing whether protection or manifestation of AD can be linked to a specific Ig isotype switch in B cells. We therefore have created AD mice that are deficient in immunoglobulins, such as IgA (5xFAD-IgAKO) or cannot generate switched Igs (5xFAD/AID-KO). In addition, we initiated attemts to enhance Abeta antibody in mice with AD. For this purpose, i.e. to enhance the generation of Abeta-specific antibody, we "converted" our DNA vaccine to RNA vaccine, a most superior strategy. The RNA vaccine was tested in 5xFAD mice at the onset of AD symptoms. Although the RNA-based vaccine generated significantly higher amounts of Abeta-specific antibody as compared to protein or DNA-based vaccine expressing the same antigen, surprisingly we failed to reverse AD symptoms. Preliminary data suggest that the vaccine may instead exacerbate the disease symptoms. To confirm and understand this unexpected result, we are repeating the experiment in a larger cohort of mice. In addition, we are reapeating the study in younger and older cohorts of 5xFAD mice. These results are in concordance with our recent finding that genetic B-cell deficiency (B-KO) blocks manifestation of AD symptoms in all three widely used transgenic AD mouse models, such as 3xTgAD, APP/PS1 and 5xFAD mice (respectively termed 3xTgAD/BKO, 2xTgAD/BKO and 5xFAD/BKO). The B-KO almost completely reversed the AD symptoms despite expression of AD-promoting transgenes. Compared to age/sex-matched B-cell sufficient littermates, 2xTgAD/BKO, 5xFAD/BKO and 3xTgAD/BKO mice exhibited reduced anxiety and improved memory deficits. 2xTgAD/BKO, 5xFAD/BKO and 3xTgAD/BKO mice contained significantly fewer A-beta plaques in the brain subiculum than their age- and sex-matched littermates. Our preliminary results indicate that 5xFAD/AID-KO mice do not affect amyloid burden nor cognitive impairments, implying that AD progresses despite the loss of secreted Igs. We did not test 5xFAD/IgA-KO mice yet, as due to loss of our breeder pairs during the COVID19 pandemic, the strain had to be rederived. Overall, the project is progressing, and some results of the study have been included in our recent manuscript submitted for publication (Wang et al., 2023).
Terms: <AD dementia><AD transgenic mice><APP-PS1><APP/PS1><Age><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease transgenic mice><Alzheimer's transgenic mice><Alzheimers Dementia><Amentia><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Antibodies><Antigens><Aβ><Aβ burden><B blood cells><B cell><B cells><B-Cell Activation><B-Cell Deficiency><B-Cells><B-Lymphocytes><B-cell><B220><Blood><Blood Reticuloendothelial System><Brain><Brain Inflammation><Brain Nervous System><CD45><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 public health crisis><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 pandemic><COVID19 public health crisis><Cell Body><Cells><Class Switching><Class Switchings><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><DNA><DNA Vaccines><Data><Dementia><Deoxyribonucleic Acid><Disease><Disease Progression><Disorder><Disturbance in cognition><Down Syndrome><Down's Syndrome><Downs Syndrome><Elderly><Encephalitis><Encephalon><Exhibits><GP180><Generations><Genetic><Goals><Hortega cell><IgA><Immune><Immune Globulins><Immunes><Immunoglobulin A><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin Isotypes><Immunoglobulins><Impaired cognition><Insulin Resistance><Isotype Switching><Isotype Switchings><KO mice><Knock-out Mice><Knockout Mice><LY5><Langdon Down syndrome><Link><Manuscripts><Memory Deficit><Memory impairment><Mice><Mice Mammals><Microglia><Mongolism><Murine><Mus><Naked DNA Vaccines><Nature><Null Mouse><PTPRC><PTPRC gene><Pathogenicity><Primary Senile Degenerative Dementia><Proteins><Publications><RNA vaccine><RNA-based vaccine><Recombinant DNA Vaccines><Role><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV2 epidemic><SARS-CoV2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Scientific Publication><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Staining method><Stains><Symptoms><T200><Testing><Transgenes><Translational Research><Translational Science><Trisomy 21><Vaccines><a beta peptide><a-beta burden><abeta><abeta burden><activated B cells><advanced age><ages><amyloid beta><amyloid burden><amyloid-b protein><anti-CD20><anxiety reduction><beta amyloid burden><beta amyloid fibril><chromosome 21 trisomy syndrome><cognitive dysfunction><cognitive loss><cohort><congenital acromicria syndrome><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><elders><experiment><experimental research><experimental study><experiments><geriatric><gitter cell><humoral immunity deficiency><immunogen><improved><insulin resistant><late life><later life><mRNA vaccine><mRNA-based vaccine><memory dysfunction><mesoglia><microglial cell><microgliocyte><morbus Down><mouse model><murine model><older adult><older person><perivascular glial cell><primary degenerative dementia><pseudohypertrophic progressive muscular dystrophy><senile dementia of the Alzheimer type><senior citizen><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex><social role><soluble amyloid precursor protein><transgene><translation research><translational investigation><trisomy 21 syndrome><β-amyloid burden><βamyloid burden>