Biology subjects

Cordi, C. V.

Publications and source records attributed to Cordi, C. V..

3 recordsLinked to original sources

bioRxiv2026

Circadian disruption induces sex-specific Alzheimer's pathophysiology and immune cell reprogramming

Circadian disruption (CD) is increasingly recognized as a sex-specific risk factor for Alzheimers disease (AD). However, the mechanisms linking CD to AD, and the role of biological sex in this interaction, are unclear. Immunometabolic regulation is extensively circadianly timed, has sex-specific phenotypes, and plays a role in AD. Therefore, we hypothesized that CD affects the timing of immunometabolism, contributing to the sex-specific effects of CD on AD. To demonstrate this, we subjected male and female APP/PS1 mice to chronic disruptive lighting to model circadian disruption, finding CD induced a female-specific reduction in amyloid plaque burden but an increase in the infiltration of peripheral macrophages into the brain. Concomitantly, we found macrophages exhibited CD-associated immune reprogramming, which in females led to altered immunometabolic timing, an increase of macrophages in the activated state, and elevated levels of reactive oxygen species (ROS), supporting a role for immunometabolism in the sex-specific effects of CD in AD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/721994v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@b9a59forg.highwire.dtl.DTLVardef@289219org.highwire.dtl.DTLVardef@18fe804org.highwire.dtl.DTLVardef@c96bb8_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICircadian disruption reduces A{beta} plaque load specifically in female mice C_LIO_LIPeripheral immune infiltration correlates with reduced A{beta} plaques in females C_LIO_LICircadian disruption coordinates phasing of circadian immunometabolic proteins C_LIO_LIIn females, circadian phase advancement correlates with increased ROS C_LI

molecular biology↗

bioRxiv2026

Alzheimer's Disease and circadian disruption sex-specifically contribute to a loss of bone maintenance in APP/PS1 model mice

Alzheimers Disease and Related Dementias (ADRDs) are linked to reduced bone integrity and increased fracture risk, but the mechanisms that underlie this risk remain poorly defined. Current research suggests that environmental factors, such as diet, sleep, and light exposure can modulate the brain-bone axis, increasing susceptibility to bone loss and fractures. Circadian disruption (CD) associated with ADRDs may exacerbate the effects of disease and aging in the bone. In particular, regulation of bone marrow progenitors may be acutely susceptible to disruption along this axis. Here, we explore the interplay among genetic and environmental factors that influence bone structure, marrow progenitor cell activity, and monocyte-derived macrophages. The APP/PS1 transgenic mouse model (AP) is used as an in vivo model of amyloid-beta deposition. High-resolution micro-computed tomography (CT) identified sex- and genotype-specific responses in trabecular morphometry. Follow-up analysis with Raman spectroscopy (RS) found accumulation of non-enzymatic modifications of the organic matrix and notched three-point bending identified concomitant loss of bone toughness due to both CD and AP. Single-cell RNA sequencing (scRNA-seq) confirmed the presence of oxidative stress signals in the cellular populations of the bone marrow. We further mapped significantly differentially expressed genes (DEGs) from monocytes in the bone marrow to circadian-regulated proteins in monocyte-derived macrophages, revealing dysregulation of circadian timing in macrophages in vitro. These findings offer new insights into how environmental disruptions can exacerbate the progression of neurodegenerative disease and bone degradation. LAY SUMMARYPatients with Alzheimers disease have an increased bone fracture risk, but the biological link between brain and bone disease is not well understood. Everyday factors such as altered light exposure (shift work, screens late at night, etc.) can worsen outcomes in the brain and skeleton. Using a mouse model of Alzheimers disease, we found that both genetic risk and circadian disruption contribute to weaker bone and altered bone quality. We also identified inflammation and stress responses in bone marrow cells, suggesting that bone marrow may play a key role in linking brain disease to bone fragility.

bioengineering↗

bioRxiv2023

Identifying Fibrogenic Cells Following Salivary Gland Obstructive Injury

Fibrosis results from excess extracellular matrix accumulation, which alters normal tissue architecture and impedes function. In the salivary gland, fibrosis can be induced by irradiation treatment for cancer therapy, Sjogrens Disease, and other causes; however, it is unclear which stromal cells and signals participate in injury responses and disease progression. As hedgehog signaling has been implicated in fibrosis of the salivary gland and other organs, we examined contributions of the hedgehog effector, Gli1, to fibrotic responses in salivary glands. To experimentally induce a fibrotic response in female murine submandibular salivary glands, we performed ductal ligation surgery. We detected a progressive fibrotic response where both extracellular matrix accumulation and actively remodeled collagen trended upwards at 7 days and significantly increased at 14 days post- ligation. Macrophages, which participate in extracellular matrix remodeling, Gli1+ and PDGFR+ stromal cells, which may deposit extracellular matrix, both increased with injury. Using single-cell RNA-sequencing, we found that a majority of Gli1+ cells at embryonic day 16 also express Pdgfra and/or Pdgfrb. However, in adult mice, only a small subset of Gli1+ cells express PDGFR and/or PDGFR{beta} at the protein level. Using lineage-tracing mice, we found that Gli1-derived cells expand with ductal ligation injury. Although some of the Gli1 lineage-traced tdTomato+ cells expressed vimentin and PDGFR{beta} following injury, there was no increase in the classic myofibroblast marker, smooth muscle alpha-actin. Additionally, there was little change in extracellular matrix area, remodeled collagen area, PDGFR, PDGFR{beta}, endothelial cells, neurons, or macrophages in Gli1 null salivary glands following injury when compared with controls, suggesting that Gli1 signaling and Gli1+ cells have only a minor contribution to mechanical injury-induced fibrotic changes in the salivary gland. We used scRNA-seq to examine cell populations that expand with ligation and/or showed increased expression of matrisome genes. Pdgfra+/Pdgfrb+ stromal cell subpopulations both expanded in response to ligation, showed increased expression and a greater diversity of matrisome genes expressed, consistent with these cells being fibrogenic. Defining the signaling pathways driving fibrotic responses in stromal cell sub-types could reveal future therapeutic targets.

cell biology↗