Chronic hypoxia of endothelial cells boosts HIF-1α-NLRP1 circuit in Alzheimer's disease.

Cerebral microvasculature of patients with Alzheimer's disease (AD) exhibits reduced capillary diameter and impaired blood flow. Molecular mechanisms of ischemic vessels affecting AD progressions have not been well established yet. In the present study, we found that in vivo triple (PS1M146V, APPswe, tauP301L) transgenic AD mouse model (3x-Tg AD) brains and retinas showed hypoxic vessels expressing hypoxyprobe and hypoxia inducible factor-1α (HIF-1α). To mimic in vivo hypoxic vessels, we used in vitro oxygen-glucose deprivation (OGD)-treated endothelial cells. HIF-1α protein was increased through reactive oxygen species (ROS) producing NADPH oxidases (NOX) (i.e., Nox2, Nox4). OGD-induced HIF-1α upregulated Nox2 and Nox4, demonstrating crosstalk between HIF-1α and NOX (i.e., Nox2, Nox4). Interestingly, NLR family pyrin domain containing 1 (NLRP1) protein was promoted by OGD, and such effect was blocked by downregulation of Nox4 and HIF-1α. Knockdown of NLRP1 also diminished OGD-mediated protein levels of Nox2, Nox4, and HIF-1α in human brain microvascular endothelial cells. These results showed interplay among HIF-1α, Nox4 and NLRP1 in OGD-treated endothelial cells. Expression of NLRP3 was not detected well in hypoxic endothelial cells of 3x-Tg AD retinas or OGD-treated endothelial cells. Instead, hypoxic endothelial cells of 3x-Tg AD brains and retinas markedly expressed NLRP1, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), caspase-1, and interleukin-1ß (IL-1ß). Taken together, our results suggest that AD brains and retinas can trigger chronic hypoxia especially in microvascular endothelial cells, consequently leading to NLRP1 inflammasome formation and upregulation of ASC-caspase-1-IL-1ß cascades. In addition, NLRP1 can stimulate HIF-1α expression and form HIF-1α-NLRP1 circuit. These consequences might further destroy vascular system in AD.

Regenerative Potential of Carbon Monoxide in Adult Neural Circuits of the Central Nervous System.

Regeneration of adult neural circuits after an injury is limited in the central nervous system (CNS). Heme oxygenase (HO) is an enzyme that produces HO metabolites, such as carbon monoxide (CO), biliverdin and iron by heme degradation. CO may act as a biological signal transduction effector in CNS regeneration by stimulating neuronal intrinsic and extrinsic mechanisms as well as mitochondrial biogenesis. CO may give directions by which the injured neurovascular system switches into regeneration mode by stimulating endogenous neural stem cells and endothelial cells to produce neurons and vessels capable of replacing injured neurons and vessels in the CNS. The present review discusses the regenerative potential of CO in acute and chronic neuroinflammatory diseases of the CNS, such as stroke, traumatic brain injury, multiple sclerosis and Alzheimer's disease and the role of signaling pathways and neurotrophic factors. CO-mediated facilitation of cellular communications may boost regeneration, consequently forming functional adult neural circuits in CNS injury.