A calvarial stem cell mediating a new bone-brain axis in Alzheimer's disease - Project Summary Despite advancements in the therapeutic targeting of amyloid beta (Aβ), Alzheimer's disease (AD) remains a persistent clinical challenge. Neuroinflammation, an early AD marker, emphasizes the need to comprehend and regulate crosstalk between the central nervous system (CNS) and the immune system. Beyond microglia, CNS-infiltrating leukocytes play a role, yet the mechanisms governing their brain entry and antigenic priming remain elusive. Recent findings highlighting the calvarial bone marrow as a source of these leukocytes suggest that regulating the calvarial marrow environment may be a crucial, overlooked element in AD pathogenesis. However, the skeletal cells responsible for forming this environment remain unknown. Our prior research identified two distinct skeletal stem cell (SSC) populations in the calvarium, essential for calvarium formation but incapable of marrow formation. Building upon this foundation, we recently discovered a novel SSC type with the capacity to support hematopoiesis within the calvarium. Disrupting the function of this SSC in mice suppressed calvarial marrow formation, leading to a 70% reduction in leukocytes. Notably, this SSC deficiency coincided with diminished immune cell infiltration and microglial abundance in the brain of an AD mouse model. Within the calvarium, these SSCs orchestrate the creation of a unique marrow environment, characterized by the presence of previously unidentified cellular elements, including previously unrecognized antigen-presenting cells not found in other skeletal marrow regions. Driven by these findings, we will investigate the critical role of these marrow-forming SSCs in establishing a unique marrow niche and understanding its influence on AD progression, as outlined in the following aims: In Aim 1, we will determine the role of newly identified calvarial SSC in CNS immunopathology by genetically manipulating this SSC and assessing the impact on the progression of AD models. We will further determine whether treatment with FDA-approved osteoporosis drugs targeting this stem cell impacts AD progression and thereby offer a rapid path for clinical translation of our findings. In Aim 2, we will determine how the unique cellular characteristics of the calvarial marrow environment, orchestrated by these SSCs, modulate AD progression. In particular, we will investigate how a population of calvarial antigen-presenting cells we have newly identified in conjunction with this SSC contributes to AD pathogenesis. Lastly, in Aim 3, we will determine if the calvarial marrow properties observed in mice translate to humans. This will involve a combined approach using autopsy and surgical specimens to identify the human counterparts of these novel calvarial SSCs and other unique calvarial features, such as the presence of calvarial the specialized calvarial antigen-presenting cells identified above in mice. Altogether, this project will establish the major new concept that a specific new calvarial stem cell regulates immune function in the brain, thereby providing new therapeutic opportunities to slow the progression of neurodegenerative diseases of aging.
