Background: Human islet amyloid polypeptide (hIAPP) fibrils of unknown structure are formed in type 2 diabetes. Results: A hIAPP fibril structure was derived from EPR data, electron microscopy, and computer modeling. Conclusion:The fibril is a left-handed helix that contains hIAPP monomers in a staggered conformation. Significance: The results provide the basis for therapeutic prevention of fibril formation and growth.

Type 2 diabetes involves aberrant misfolding of human islet amyloid polypeptide (h-IAPP) and resultant pancreatic amyloid deposits. Curcumin, a biphenolic small molecule, has offered potential benefits in other protein misfolding diseases, such as Alzheimer’s disease. Our aim was to investigate whether curcumin alters h-IAPP misfolding and protects from cellular toxicity at physiologically relevant concentrations. The effect of curcumin on h-IAPP misfolding in vitro was investigated by electron paramagnetic resonance spectroscopy, ThT fluorescence and electron microscopy. Our in vitro studies revealed that curcumin significantly reduces h-IAPP fibril formation and aggregates formed in the presence of curcumin display alternative morphology and structure. We then tested a potential protective effect of curcumin against h-IAPP toxicity on β-cells. Micromolar concentrations of curcumin partially protect INS cells from exogenous IAPP toxicity. This protective effect, however, is limited to a narrow concentration range, as curcumin becomes cytotoxic at micromolar concentrations. In different models of endogenous over-expression of h-IAPP (INS cells and h-IAPP transgenic rat islets), curcumin failed to protect β-cells from h-IAPP-induced apoptosis. While curcumin has the ability to inhibit amyloid formation, the present data suggest that, without further modification, it is unlikely to be therapeutically useful in protection of β-cells in type 2 diabetes.

PURPOSE. The purpose of this study was to measure change in anterior lamina cribrosa depth (ALD) globally and regionally in glaucoma eyes at different intraocular pressures (IOP).METHODS. Twenty-seven glaucoma patients were imaged before and after IOP-lowering procedures using optical coherence tomography. The anterior lamina was marked in approximately 25 locations in each of six radial scans to obtain global and regional estimates of ALD. ALD and its change with IOP were compared with optic disc damage, nerve fiber layer thickness, and visual field loss. RESULTS.Variables associated with deeper baseline ALD included larger cup/disc ratio, thinner rim area, larger cup volume, thinner central corneal thickness, and male sex (all P 0.02). When IOP was lowered, ALD position became more anterior, more posterior, or was unchanged. The mean ALD change after lowering was 27 6 142 lm (P ¼ 0.3). The mean absolute value of ALD change was 112 6 90 lm (P ¼ 0.002). Change in ALD was greater in eyes with lower IOP in paired comparisons (P ¼ 0.006) but was not associated with the magnitude of IOP lowering between imaging sessions (P ¼ 0.94). Eyes with no significant change in ALD tended to have more visual field loss than those with significant anterior ALD displacement (P ¼ 0.07). Areas within each optic nerve head that corresponded to zones with thicker nerve fiber layer had greater ALD positional change (P ¼ 0.0007).CONCLUSIONS. The lamina can move either anteriorly or posteriorly with IOP decrease, with greater displacement at lower IOP. Glaucoma eyes and regions within glaucoma eyes associated with greater glaucoma damage exhibited smaller responses.Keywords: glaucoma, lamina cribrosa, optic nerve head, optical coherence tomography, intraocular pressure, biomechanics, stress A major site of damage to retinal ganglion cell (RGC) axons in glaucoma is the optic nerve head (ONH), within the lamina cribrosa.1-3 The biomechanical transmission of stress from intraocular pressure (IOP) produces strain in both the sclera and the ONH, 4-6 generating detrimental effects on RGC axons, ONH astrocytes, and nutritional blood flow in the nerve head. 7 The IOP level that produces RGC loss can be variable among individuals; some eyes suffer damage at IOPs that would be considered normal based on population studies, whereas many eyes with elevated IOP suffer no detectable damage. This suggests that the short-and long-term responses of scleral and ONH connective tissues to changes in IOP represent possible biomarkers for glaucoma incidence and progression. Normal lamina cribrosa structure is remodeled in glaucoma eyes, becoming deeper and wider 8 under the influence of a variety of factors, notably the stress of IOP as delivered through the sclera. 9 The regional differences in connective tissue density and pore size within the lamina cribrosa and greater regional strains suggest that the upper and lower poles of the ONH are weaker at resisting the stress of IOP in both human 10-14 and nonhuman primate eyes. 15 Indeed, these regions contain...

PurposeTo compare the diagnostic ability of the vessel parameters in macular and peripapillary regions measured using spectral-domain optical coherence tomography angiography (SD-OCTA) in differentiating primary open-angle glaucoma (POAG) from healthy eyes.MethodsPOAG patients and healthy subjects underwent 6 × 6-mm scans centered on the macula and optic nerve head. Commercially available automatic segmentation created en face images from SD-OCTA of the superficial retinal layer (SRL) of the macular (m) and peripapillary (cp) regions. Vessel area density (VAD), vessel skeleton density (VSD), vessel complexity index (VCI), and flux were calculated. Area under curve (AUC) statistics controlled for age and intereye correlation.ResultsOf 126 eyes from 79 patients who underwent SD-OCTA macula and peripapillary imaging, 50 eyes from 35 POAG patients and 37 healthy eyes from 25 control subjects had good quality imaging and were studied. Diagnostic accuracies of four perfusion parameters, VAD, VSD, VCI, and flux, were significantly greater in the peripapillary compared with the macular regions. For VAD, the cpAUC was 0.84 and mAUC was 0.73 (AUC difference: P = 0.026). For VSD, the cpAUC was 0.84 and mAUC was 0.72 (ΔP = 0.015). For VCI, the cpAUC was 0.80 and mAUC was 0.70 (ΔP = 0.045). For flux, the cpAUC = 0.87 and mAUC was 0.76 (ΔP = 0.0091).ConclusionsPeripapillary perfusion parameters performed better than macular perfusion parameters for glaucoma diagnosis, supporting the idea that glaucomatous superficial retinal vascular changes are more pronounced in the peripapillary region.Translational RelevanceThe diagnostic accuracy of OCTA perfusion parameters of the superficial retinal microcirculation was greater for the peripapillary region than the macular region in the diagnosis of glaucoma.