Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.

Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation.

/YKL-40 is controlled by the astrocyte circadian clock and regulates neuroinflammation and Alzheimer's disease pathogenesis.

Regulation of glial activation and neuroinflammation are critical factors in the pathogenesis of Alzheimer's disease (AD). YKL-40, a primarily astrocytic protein encoded by the gene , is a widely studied cerebrospinal fluid biomarker that increases with aging and early in AD. However, the function of /YKL-40 in AD is unknown.

REV-ERBα mediates complement expression and diurnal regulation of microglial synaptic phagocytosis.

The circadian clock regulates various aspects of brain health including microglial and astrocyte activation. Here, we report that deletion of the master clock protein BMAL1 in mice robustly increases expression of complement genes, including and , in the hippocampus. BMAL1 regulates expression of the transcriptional repressor REV-ERBα, and deletion of REV-ERBα causes increased expression of transcript in neurons and astrocytes as well as C3 protein primarily in astrocytes.

Rev-erbs and Glia-Implications for Neurodegenerative Diseases.

Recently, we described a role for the circadian clock protein and nuclear receptor Rev-erbα in regulating glial activation states in the brain. Deletion of Rev-erbα resulted in microglial as well as astrocytic activation, while a Rev-erbα agonist diminished the severity of lipopolysaccharide (LPS)-induced neuroinflammation. Concomitant with this glial activation is impaired neuronal health.

Circadian clock protein Rev-erbα regulates neuroinflammation.

Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation.

Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1.

Circadian clock dysfunction is a common symptom of aging and neurodegenerative diseases, though its impact on brain health is poorly understood. Astrocyte activation occurs in response to diverse insults and plays a critical role in brain health and disease. We report that the core circadian clock protein BMAL1 regulates astrogliosis in a synergistic manner via a cell-autonomous mechanism and a lesser non-cell-autonomous signal from neurons.

Regulation of amyloid-β dynamics and pathology by the circadian clock.

Nighttime restlessness and daytime drowsiness are common and early symptoms of Alzheimer's Disease (AD). This symptomology implicates dysfunctional biological timing, yet the role of the circadian system in AD pathogenesis is unknown. To evaluate the role of the circadian clock in amyloid-β (Aβ) dynamics and pathology, we used a mouse model of β-amyloidosis and disrupted circadian clock function either globally or locally in the brain via targeted deletion of the core clock gene Our results demonstrate that loss of central circadian rhythms leads to disruption of daily hippocampal interstitial fluid Aβ oscillations and accelerates amyloid plaque accumulation, whereas loss of peripheral in the brain parenchyma increases expression of and promotes fibrillar plaque deposition.

Imaging of CD47 expression in xenograft and allograft tumor models.

CD47 functions as a marker of "self" by inhibiting phagocytosis of autologous cells. CD47 has been shown to be overexpressed by various tumor types as a means of escaping the antitumor immune response. The goal of this research was to investigate the utility of CD47 imaging using positron emission tomography (PET) in both human xenograft and murine allograft tumor models.

Age-dependent regulation of skeletal muscle mitochondria by the thrombospondin-1 receptor CD47.

CD47, a receptor for thrombospondin-1, limits two important regulatory axes: nitric oxide-cGMP signaling and cAMP signaling, both of which can promote mitochondrial biogenesis. Electron microscopy revealed increased mitochondrial densities in skeletal muscle from both CD47 null and thrombospondin-1 null mice. We further assessed the mitochondria status of CD47-null vs WT mice.

A naturally occurring extracellular alpha-beta clasp contributes to stabilization of beta3 integrins in a bent, resting conformation.

Control of alphaIIb beta3 and alphav beta3 integrin activation is critical for cardiovascular homeostasis. Mutations that perturb association of integrin alpha and beta subunits in their transmembrane and cytoplasmic regions activate the integrin heterodimer, suggesting that a low-affinity or "off" conformation is the default state, likely corresponding to the bent conformation seen in the crystal structure of alphav beta3. In this bent structure, a segment of alphav (301-308) and beta3 (560-567) are juxtaposed.

CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1.

CD36 is necessary for inhibition of some angiogenic responses by the matricellular glycoprotein thrombospondin-1 and is therefore assumed to be the receptor that mediates its anti-angiogenic activities. Although ligation of CD36 by antibodies, recombinant type 1 repeats of thrombospondin-1, or CD36-binding peptides was sufficient to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells, picomolar concentrations of native thrombospondin-1 similarly inhibited NO signaling in vascular cells from wild-type and CD36-null mice. Ligation of the thrombospondin-1 receptor CD47 by recombinant C-terminal regions of thrombospondin-1, thrombospondin-1 peptides, or CD47 antibodies was also sufficient to inhibit NO-stimulated phenotypic responses and cGMP signaling in vascular cells.

CD47 augments Fas/CD95-mediated apoptosis.

Fas (CD95) mediates apoptosis of many cell types, but the susceptibility of cells to killing by Fas ligand and anti-Fas antibodies is highly variable. Jurkat T cells lacking CD47 (integrin-associated protein) are relatively resistant to Fas-mediated death but are efficiently killed by Fas ligand or anti-Fas IgM (CH11) upon expression of CD47. Lack of CD47 impairs events downstream of Fas activation including caspase activation, poly-(ADP-ribose) polymerase cleavage, cytochrome c release from mitochondria, loss of mitochondrial membrane potential, and DNA cleavage.