Failure of Alzheimer’s Mice Brain Resident Neural Precursor Cells in Supporting Microglia-Mediated Amyloid β Clearance

The failure of brain microglia to clear excess amyloid β (Aβ) is considered a leading cause of the progression of Alzheimer’s disease pathology. Resident brain neural precursor cells (NPCs) possess immune-modulatory and neuro-protective properties, which are thought to maintain brain homeostasis. We have recently showed that resident mouse brain NPCs exhibit an acquired decline in their trophic properties in the Alzheimer’s disease brain environment. Therefore, we hypothesized that functional NPCs may support microglial phagocytic activity, and that NPCs derived from the adult AD mouse brain may fail to support the clearance of Aβ by microglia. We first identified in the AD brain, in vivo and ex vivo, a subpopulation of microglia that express high Aβ phagocytic activity. Time-lapse microscopy showed that co-culturing newborn NPCs with microglia induced a significant increase in the fraction of microglia with high Aβ phagocytic activity. Freshly isolated NPCs from adult wild type, but not AD, mouse brain, induced an increase in the fraction of microglia with high Aβ phagocytic activity. Finally, we showed that NPCs also possess the ability to promote Aβ degradation within the microglia with high Aβ phagocytic activity. Thus, resident brain NPCs support microglial function to clear Aβ, but NPCs derived from the AD environment fail to do so. We suggest that the failure of AD brain NPCs to support Aβ clearance from the brain by microglia may accelerate disease pathology

SuperDopa (SD), SuperDopa amide (SDA) and Thioredoxin-mimetic peptides protect ARPE-19 cells from photic- and non-photic stress

Oxidative stress and inflammation in the retinal pigment epithelium (RPE) cells have been identified as significant risk factors in the development and progression of retinal associated diseases including age-related macular degeneration (AMD). In addition, AMD and myopia have been associated with impaired dopamine activity. Treatment of RPE cells with antioxidants or high concentrations of l-DOPA (levodopa), which down-regulates vascular endothelial growth factor (VEGF) via a G-protein-coupled receptor GPR143, slow AMD progression. To develop a targeted and effective treatment aimed at improving the viability of RPE cells we examined small molecular weight thiol-based and levodopa containing molecules. These include the N-acetylcysteine amide (AD4/NACA), SuperDopa-Amide (SDA), and members of the thioredoxin mimetic (TXM) family of peptides, TXM-CB13, TXM-CB30, and SuperDopa (SD). We show that these antioxidant/anti-inflammatory reagents protect ARPE-19 cells from photic stress mediated by rose Bengal (rB) and rhodopsin-rich POS, and from non-photic stress induced by oxidation with sodium iodate. Protection is correlated with a reduction in DPPH radical and singlet-oxygen quenching. Compared to GSH the bimolecular rate-constants of singlet oxygen quenching in aqueous solution by the levodopa derivatives SD and SDA were two-fold higher. Inhibition of auranofin-induced activation of the mitogen-activation-kinases (MAPK's) JNK1/2 and ERK1/2 confirmed the antioxidant/anti-inflammatory activity of the thiol-levodopa derivatives. The antioxidant and radical scavenging activities of TXM-CB13 and TXM-CB30, or SD and SDA, which combine redox activity with elevating cellular levodopa, might offer an efficient protection of RPE cells. These retino-protective peptides are potential drug candidates destined for slowing the onset and/or progression of RPE-related disorders

Failure of Alzheimer’s Mice Brain Resident Neural Precursor Cells in Supporting Microglia-Mediated Amyloid β Clearance

The failure of brain microglia to clear excess amyloid β (Aβ) is considered a leading cause of the progression of Alzheimer’s disease pathology. Resident brain neural precursor cells (NPCs) possess immune-modulatory and neuro-protective properties, which are thought to maintain brain homeostasis. We have recently showed that resident mouse brain NPCs exhibit an acquired decline in their trophic properties in the Alzheimer’s disease brain environment. Therefore, we hypothesized that functional NPCs may support microglial phagocytic activity, and that NPCs derived from the adult AD mouse brain may fail to support the clearance of Aβ by microglia. We first identified in the AD brain, in vivo and ex vivo, a subpopulation of microglia that express high Aβ phagocytic activity. Time-lapse microscopy showed that co-culturing newborn NPCs with microglia induced a significant increase in the fraction of microglia with high Aβ phagocytic activity. Freshly isolated NPCs from adult wild type, but not AD, mouse brain, induced an increase in the fraction of microglia with high Aβ phagocytic activity. Finally, we showed that NPCs also possess the ability to promote Aβ degradation within the microglia with high Aβ phagocytic activity. Thus, resident brain NPCs support microglial function to clear Aβ, but NPCs derived from the AD environment fail to do so. We suggest that the failure of AD brain NPCs to support Aβ clearance from the brain by microglia may accelerate disease pathology

TXM peptides inhibit SARS-CoV-2 infection, syncytia formation, and lower inflamatory consequences

After three years of the SARS-CoV-2 pandemic, the search and availability of relatively low-cost benchtop therapeutics for people not at high risk for a severe disease are still ongoing. Although vaccines and new SARS-CoV-2 variants reduce the death toll, the long COVID-19 along with neurologic symptoms can develop and persist even after a mild initial infection. Reinfections, which further increase the risk of sequelae in multiple organ systems as well as the risk of death, continue to require caution. The spike protein of SARS-CoV-2 is an important target for both vaccines and therapeutics. The presence of disulfide bonds in the receptor binding domain (RBD) of the spike protein is essential for its binding to the human ACE2 receptor and cell entry. Here, we demonstrate that thiol-reducing peptides based on the active site of oxidoreductase thioredoxin 1, called thioredoxin mimetic (TXM) peptides, can prevent syncytia formation, SARS-CoV-2 entry into cells, and infection in a mouse model. We also show that TXM peptides inhibit the redox-sensitive HIV pseudotyped viral cell entry. These results support disulfide targeting as a common therapeutic strategy for treating infections caused by viruses using redox-sensitive fusion. Furthermore, TXM peptides exert anti-inflammatory properties by lowering the activation of NF-κB and IRF signaling pathways, mitogen-activated protein kinases (MAPKs) and lipopolysaccharide (LPS)-induced cytokines in mice. The antioxidant and anti-inflammatory effects of the TXM peptides, which also cross the blood-brain barrier, in combination with prevention of viral infections, may provide a beneficial clinical strategy to lower viral infections and mitigate severe consequences of COVID-19