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Principal Investigator: Arya Biragyn
Organization: NATIONAL INSTITUTE ON AGING
Fiscal Year: 2024
Award: $360,948
Funding agency: National Institute on Aging
According to the prevailing Amyloid cascade hypothesis, Alzheimers disease (AD) is caused by decades-long deposition of neurotoxic amyloid Ab-peptide aggregates (Ab plaques) in the brain. It leads to a chain of pathological events, including tauopathy, astrogliosis, accumulation of disease associated microglia (DAM), synaptic and neuronal dysfunction, and eventually dementia. However, the role of adaptive immunity remains unclear. Here we continue our recent discovery that the AD manifestation also depends on B cells. Contrary to the assumption that the adaptive immunity plays a negligible role in AD, we reported that the disease cannot progress if B cells are lost in 3 distinct mice with early onset of AD (EOAD) (Kim et al., Nature Comm, 2021). However, the mechanism how B cells promote AD-like pathology remains unknown.
In the present work, we tested if B cells promote AD-like pathology via inducing CD8+ T cells to infiltrate the brain. The idea is based on recent discovery of potentially pathogenic CD8+ T cells in the brain of mice and humans with tauopathy (but not amyloidosis). Contrary to assumption that amyloidosis does not cause infiltration of CD8+ T cells in the brain of 5xFAD mice, we show that CD8+ T cells significantly increase in the brain of 5xFAD mice and postmortem brains of humans with AD. In the brain parenchyma of 5xFAD mice and humans with AD, we show that CD8+ T cells mostly form complexes with microglia around Abeta plaques. Phenotypically, the brain CD8+ T cells resemble exhausted tissue resident memory cells. In-depth characterization of brain CD8+ T cells in 5xFAD mice indicate that they are CXCR6+ exhausted-like effector memory, tissue resident cells expressing IFNg and ectonucleotidases CD39 and CD73. Their signature we also find in the databases of brain snRAN-seq of humans with AD. Notably, genetic or antibody-mediated B cell ablation almost completely eliminates increase of exhausted like CD8+ cells and CD8+ T cell-microglia complexes in the brain of 5xFAD mice,suggesting that B cells could indeed be responsible for the induction of brain-infiltrating CD8+ T cells. Mechanistically, we think that upon peripheral activation with Ab peptide-presenting B cells, CD8+ T cells infiltrate the brain to to affect microglial activity. In support of this idea, immunization of 5xFAD mice with Abeta-encoding RNA vaccine increases CD8+ T cells in the brain and exacerbates AD-like pathology. Conversely, antibody-mediated depletion of CD8+ T cells reduces Brian CD8+ T cells and AD-like pathology. Overall, our data underscore overlooked role of the adaptive immunity in AD by demonstrating a pathogenic role of the B-cell-to-CD8 cell crosstalk in promoting AD-like pathology in 5xFAD mice. This project is has been submitted for publication and is currently under review in BBI (Xin et al., 2024).
Terms: <AD dementia><Ablation><Affect><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer like pathology><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease like pathology><Alzheimers Dementia><Amentia><Amyloid><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Substance><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Amyloidosis><Antibodies><Autopsy><Aβ><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><BONZO><Body Tissues><Brain><Brain Nervous System><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CXCR6><CXCR6 gene><Cell Body><Cells><Complex><Data><Data Bases><Databases><Dementia><Deposit><Deposition><Disease><Disease associated microglia><Disorder><EOAD><Early Onset Alzheimer Disease><Encephalon><Event><Genetic><Hortega cell><Human><Immunization><Infiltration><Link><Mediating><Memory><Mice><Mice Mammals><Microglia><Modern Man><Murine><Mus><Nature><Neuronal Dysfunction><Pathogenicity><Pathologic><Peptides><Peripheral><Phenotype><Play><Primary Senile Degenerative Dementia><Publications><R-Series Research Projects><R01 Mechanism><R01 Program><RNA vaccine><RNA-based vaccine><Reporting><Research Grants><Research Project Grants><Research Projects><Role><STRL33><Scientific Publication><Synapses><Synaptic><T cell infiltration><T8 Cells><T8 Lymphocytes><TYMSTR><Tauopathies><Testing><Tissues><Work><a beta peptide><abeta><adaptive immunity><amyloid beta><amyloid disease><amyloid-b protein><astrogliosis><beta amyloid fibril><brain parenchyma><data base><early onset AD><early onset Alzheimer's><ecto-nucleotidase><exhaust><gitter cell><mRNA vaccine><mRNA-based vaccine><mesoglia><microglial cell><microgliocyte><necropsy><neural dysfunction><neuropathologic tau><neuropathological tau><neurotoxic><perivascular glial cell><postmortem><primary degenerative dementia><senile dementia of the Alzheimer type><social role><soluble amyloid precursor protein><synapse><tau associated neurodegeneration><tau associated neurodegenerative process><tau induced neurodegeneration><tau mediated neurodegeneration><tau neurodegenerative disease><tau neuropathology><tauopathic neurodegenerative disorder><tauopathy>