Thursday, April 3, 2025
4/3/2025
Spontaneous and Induced B cell and T cell responses in Alzheimer's Disease - ABSTRACT Alzheimer disease (AD) is a neurodegenerative condition that causes progressive cognitive decline and death. The AD pathological hallmarks are extracellular amyloid β (Aβ) plaques and neurofibrillary tangles containing aggregated Tau protein. The US FDA recently approved aducanumab to promote Aβ plaque clearance, and antibody-mediated removal of Tau aggregates has also moved to phase II clinical trials. Despite the potential therapeutic impact of antibodies in AD, our understanding of natural B cell responses in AD remains limited. Our preliminary data demonstrate that meningeal B cells of young adult mice are not blood-borne as in aging mice, but rather derive from B cell progenitors that migrate from the skull bone marrow into the meninges and are selected by CNS antigens. Based on this premise, Aim1 will test the hypothesis that the BCR repertoire of ABand Tau-specific B cells, the affinity of the antibodies produced, and the T cell help in mouse models of Aβ plaques and tauopathy depend on the lymphopoietic niche in which they develop. Meningeal B cells derived from skull bone marrow and selected by Aβ and Tau should generate low affinity antibodies. Conversely, B cells that develop in the periphery, not selected in the CNS, should be strongly activated by Aβ and Tau, receive T cell help, and generate high affinity antibodies. Antibodies of different origins will be further tested for the ability to clear Aβ and Tau from the brain. Active Aβ immunization to induce antibody-mediated clearance of Aβ plaques has been tested in a human trial of active immunotherapy, but was discontinued because of aseptic meningoencephalitis in some cases. In this trial, Aβ peptide was injected subcutaneously together with the QS- 21 adjuvant that strongly augments T cell responses to vaccine antigens. Based on our preliminary data, Aim 2 will test the hypothesis that delivery of Aβ and Tau directly to the meninges and/or with the mild B cell selective adjuvant CpG-B will elicit anti-Aβ and Tau antibodies that clear plaques without inducing strong CNS autoimmunity. Several studies have reported that AD associates with changes in function and cytokine secretion of T cells. Our preliminary data delineates an antigen-experienced population of CD8 T cells with potent effector functions and the ability to secrete proinflammatory cytokines in the blood of AD patients, as well as clonal expansion in the CSF. Aim 3 will test the hypotheses that clonally expanding T cells are Aβ and/or Tau specific and have distinct transcriptional and phenotypic programs in AD patients versus controls; furthermore, these T cells correlate with clinical parameters. We will determine whether the BCR repertoires of Aβ- and Tau-specific B clonal expansions found in blood and CSF of AD patients and healthy controls are different and correlate with AD pathology and cognition defects. We will use innovative immunophenotyping combined with single cell TCR, BCR-, and RNA-seq methods. Results will lay the groundwork to understand anti-Aβ and anti-Tau T and B cell responses in mouse models and AD patients, which will help stratify patients before offering Aβ/Tau-based immunotherapy.
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