The rs1061170T/C variant encoding the Y402H change in complement factor H (CFH) has been identified by genome-wide association studies as being significantly associated with age-related macular degeneration (AMD). However, the precise mechanism by which this CFH variant impacts the risk of AMD remains largely unknown. Oxidative stress plays an important role in many aging diseases, including cardiovascular disease and AMD. A large amount of oxidized phospholipids (oxPLs) are generated in the eye because of sunlight exposure and high oxygen content. OxPLs bind to the retinal pigment epithelium and macrophages and strongly activate downstream inflammatory cascades. We hypothesize that CFH may impact the risk of AMD by modulating oxidative stress. Here we demonstrate that CFH binds to oxPLs. The CFH 402Y variant of the protective rs1061170 genotype binds oxPLs with a higher affinity and exhibits a stronger inhibitory effect on the binding of oxPLs to retinal pigment epithelium and macrophages. In addition, plasma from non-AMD subjects with the protective genotype has a lower level of systemic oxidative stress measured by oxPLs per apolipoprotein B (oxPLs/apoB). We also show that oxPL stimulation increases expression of genes involved in macrophage infiltration, inflammation, and neovascularization in the eye. OxPLs colocalize with CFH in drusen in the human AMD eye. Subretinal injection of oxPLs induces choroidal neovascularization in mice. In addition, we show that the CFH risk allele confers higher complement activation and cell lysis activity. Together, these findings suggest that CFH influences AMD risk by modulating oxidative stress, inflammation, and abnormal angiogenesis.

TauAmyloid b a b s t r a c t Glial glutamate transporter, GLT-1, is the major Na þ -driven glutamate transporter to control glutamate levels in synapses and prevent glutamate-induced excitotoxicity implicated in neurodegenerative disorders including Alzheimer's disease (AD). Significant functional loss of GLT-1 has been reported to correlate well with synaptic degeneration and severity of cognitive impairment among AD patients, yet the underlying molecular mechanism and its pathological consequence in AD are not well understood.Here, we find the temporal decrease in GLT-1 levels in the hippocampus of the 3xTg-AD mouse model and that the pharmacological upregulation of GLT-1 significantly ameliorates the age-dependent pathological tau accumulation, restores synaptic proteins, and rescues cognitive decline with minimal effects on Ab pathology. In primary neuron and astrocyte coculture, naturally secreted Ab species significantly downregulate GLT-1 steady-state and expression levels. Taken together, our data strongly suggest that GLT-1 restoration is neuroprotective and Ab-induced astrocyte dysfunction represented by a functional loss of GLT-1 may serve as one of the major pathological links between Ab and tau pathology.

Background: Genetic variants of high temperature requirement factor A1 (HTRA1) associate with AMD risk. Results: Growth differentiation factor 6 (GDF6) gene polymorphism significantly associated with AMD. HTRA1 knock-out mice display reduced blood vessel in retina and up-regulation of GDF6. Conclusion: HTRA1 regulates angiogenesis via TGF-␤ signaling by GDF6, a novel disease gene. Significance: This novel pathway of HTRA1 in regulation of vascularization is critical for understanding AMD pathogenesis.

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Food-drug interactions have been associated with clinically important pharmacokinetic and pharmacodynamic changes of a drug. The aim of this paper is to review the regulation of P-glycoprotein (P-gp) by dietary components and to correlate the changes in cellular P-gp function and expression with drug bioavailability. In summary, the published literature has provided extensive data supporting the modulation of drug bioavailability through P-gp regulation by components in food groups such as fruit juices, spices, herbs, cruciferous vegetables and green tea. Most of these data were, however, derived from in vitro cell models and, except for the St John's wort, the clinical significance of most reported interactions remains to be clarified. Studies on piperine and capsaicin have underscored an often poor correlation between in vivo and in vitro data, whereas experiments involving curcumin highlighted differences between acute and chronic consumption of a dietary component on P-gp function and expression in vivo. A better understanding of the pharmacokinetic and pharmacodynamic profiles of the dietary components will aid in addressing these knowledge gaps.

Chronic exposure to copper and its dyshomeostasis have been linked to accelerated cognitive decline and potentially increasing risk for Alzheimer's disease (AD). We and others have previously demonstrated that exposure to copper through drinking water significantly increased parenchymal amyloid-beta (Ab) plaques and decreased endothelial low-density lipoprotein receptor-related protein 1 (LRP1) in mouse models of AD. In this study, we determined the underlying mechanisms that microRNA critically mediated the copper-induced loss of endothelial LRP1. In human primary microvascular endothelial cells (MVECs), were significantly elevated within the 24-h exposure to copper and returned to baseline after 48-h postexposure, which corresponded with the temporal change of LRP1 expression in these cells. Transient expression of synthetic microRNA-200b-3p, -200c-3p, or -205-5p on MVECs significantly decreased endothelial LRP1, and cotreatment of synthetic antagomirs effectively prevented the loss of LRP1 during copper exposure, collectively supporting the key regulatory role of these microRNAs in copper-induced loss of LRP1. In mice, a significant reduction of LRP1 in cortical vasculature was evident following 9 months exposure to 1.3 ppm copper in drinking water, although the levels of cortical were only marginally elevated. This, however, correlated with increased vascular accumulation of Ab and impairment of spatial memory, indicating that copper exposure has the pivotal role in the vascular damage and development of cognitive decline.

There is currently no FDA-approved therapy for treating patients with geographic atrophy (GA), a late stage of age-related macular degeneration (AMD). Cell transplantation has the potential to restore vision in these patients. This review discusses how recent advancement in induced pluripotent stem (iPS) cells provides a promising therapy for GA treatment. Recent advances in stem cell biology have demonstrated that it is possible to derive iPS cells from human somatic cells by introducing reprogramming factors. Human retinal pigment epithelium (RPE) cells and photoreceptors can be derived from iPS cells by defined factors. Studies show that transplanting these cells can stabilize or recover vision in animal models. However, cell derivation protocols and transplantation procedures still need to be optimized. Much validation has to be done before clinical-grade, patient-derived iPS can be applied for human therapy. For now, RPE cells and photoreceptors derived from patient-specific iPS cells can serve as a valuable tool in elucidating the mechanism of pathogenesis and drug discovery for GA.

Emerging evidence have posited that dysregulated microglia impair clearance and containment of amyloid-β (Aβ) species in the brain, resulting in aberrant buildup of Aβ and onset of Alzheimer’s disease (AD). Hematopoietic cell kinase (Hck) is one of the key regulators of phagocytosis among the Src family tyrosine kinases (SFKs) in myeloid cells, and its expression is found to be significantly altered in AD brains. However, the role of Hck signaling in AD pathogenesis is unknown. We employed pharmacological inhibition and genetic ablation of Hck in BV2 microglial cells and J20 mouse model of AD, respectively, to evaluate the impact of Hck deficiency on Aβ-stimulated microglial phagocytosis, Aβ clearance and resultant AD-like neuropathology. Our in vitro data reveal that pharmacological inhibition of SFKs/Hck in BV2 cells and genetic ablation of their downstream kinase, spleen tyrosine kinase (Syk), in primary microglia significantly attenuate Aβ oligomers-stimulated microglial phagocytosis. Whereas in Hck-deficient J20 mice, we observed exacerbated Aβ plaque burden, reduced microglial coverage, containment and phagocytosis of Aβ plaques, and induced iNOS expression in plaque-associated microglial clusters. These multifactorial changes in microglial activities led to attenuated PSD95 levels in hippocampal DG and CA3 regions, but did not alter the post-synaptic dendritic spine morphology at the CA1 region nor cognition function of the mice. Hck inhibition thus accelerates early stage AD-like neuropathology by dysregulating microglial function and inducing neuroinflammation. Our data implicate that Hck pathway plays a prominent role in regulating microglial neuroprotective function during the early stage of AD development.