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.

Grant Number: 1K99AG090732-01
NIH Institute/Center: NIH
Principal Investigator: Seoyeon Bok