Selective Area Deposited Blue GaN-InGaN Multiple-Quantum Well Light Emitting Diodes over Silicon Substrates

We report on fabrication and characterization of blue GaN–InGaN multi-quantum well (MQW)light-emitting diodes(LEDs) over (111) silicon substrates. Device epilayers were fabricated using unique combination of molecular beam epitaxy and low-pressure metalorganic chemical vapor depositiongrowth procedure in selective areas defined by openings in a SiO2mask over the substrates. This selective area deposition procedure in principle can produce multicolor devices using a very simple fabrication procedure. The LEDs had a peak emission wavelength of 465 nm with a full width at half maximum of 40 nm. We also present the spectral emission data with the diodes operating up to 250 °C. The peak emission wavelengths are measured as a function of both dc and pulse bias current and plate temperature to estimate the thermal impedance

Copper Accumulation and the Effect of Chelation Treatment on Cerebral Amyloid Angiopathy Compared to Parenchymal Amyloid Plaques

Accumulation of fibrillar amyloid β-protein (Aβ) in parenchymal plaques and in blood vessels of the brain, the latter condition known as cerebral amyloid angiopathy (CAA), are hallmark pathologies of Alzheimer\u27s disease (AD) and related disorders. Cerebral amyloid deposits have been reported to accumulate various metals, most notably copper and zinc. Here we show that, in human AD, copper is preferentially accumulated in amyloid-containing brain blood vessels compared to parenchymal amyloid plaques. In light of this observation, we evaluated the effects of reducing copper levels in Tg2576 mice, a transgenic model of AD amyloid pathologies. The copper chelator, tetrathiomolybdate (TTM), was administered to twelve month old Tg2576 mice for a period of five months. Copper chelation treatment significantly reduced both CAA and parenchymal plaque load in Tg2576 mice. Further, copper chelation reduced parenchymal plaque copper content but had no effect on CAA copper levels in this model. These findings indicate that copper is associated with both CAA deposits and parenchymal amyloid plaques in humans, but less in Tg2576 mice. TTM only reduces copper levels in plaques in Tg2576 mice. Reducing copper levels in the brain may beneficially lower amyloid pathologies associated with AD

Long-term voluntary wheel running does not alter vascular amyloid burden but reduces neuroinflammation in the Tg-SwDI mouse model of cerebral amyloid angiopathy

Background: Cardiovascular exercise (CVE) has been shown to be protective against cognitive decline in aging and the risk for dementias, including Alzheimer’s Disease (AD). CVE has also been shown to have several beneficial effects on brain pathology and behavioral impairments in mouse models of AD; however, no studies have specifically examined the effects of CVE on cerebral amyloid angiopathy (CAA), which is the accumulation of amyloid-beta (Aβ) in the cerebral vasculature. CAA may be uniquely susceptible to beneficial effects of CVE interventions due to the location and nature of the pathology. Alternatively, CVE may exacerbate CAA pathology, due to added stress on already compromised cerebral vasculature. Methods: In the current study, we examined the effects of CVE over many months in mice, thereby modeling a lifelong commitment to CVE in humans. We assessed this voluntary CVE in Tg-SwDI mice, a transgenic mouse model of CAA that exhibits behavioral deficits, fibrillar vascular Aβ pathology, and significant perivascular neuroinflammation. Various “doses” of exercise intervention (0 h (“Sedentary”), 1 h, 3 h, 12 h access to running wheel) were assessed from ~ 4 to 12 months of age for effects on physiology, behavior/cognitive performance, and pathology. Results: The 12 h group performed the greatest volume of exercise, whereas the 1 h and 3 h groups showed high levels of exercise intensity, as defined by more frequent and longer duration running bouts. Tg-SwDI mice exhibited significant cerebral vascular Aβ pathology and increased expression of pro-inflammatory cytokines as compared to WT controls. Tg-SwDI mice did not show motor dysfunction or altered levels of anxiety or sociability compared to WT controls, though Tg-SwDI animals did appear to exhibit a reduced tendency to explore novel environments. At all running levels, CAA pathology in Tg-SwDI mice was not significantly altered, but 12-h high-volume exercise showed increased insoluble Aβ burden. However, CVE attenuated the expression of pro-inflammatory cytokines TNF-α and IL-6 and was generally effective at enhancing motor function and reducing anxiety-like behavior in Tg-SwDI mice, though alterations in learning and memory tasks were varied. Conclusions: Taken together, these results suggest that CAA can still develop regardless of a lifespan of substantial CVE, although downstream effects on neuroinflammation may be reduced and functional outcomes improved

Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy

Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer’s disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aβ deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss

Expanded encyclopaedias of DNA elements in the human and mouse genomes

All data are available on the ENCODE data portal: www.encodeproject. org. All code is available on GitHub from the links provided in the methods section. Code related to the Registry of cCREs can be found at https:// github.com/weng-lab/ENCODE-cCREs. Code related to SCREEN can be found at https://github.com/weng-lab/SCREEN.© The Author(s) 2020. The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.This work was supported by grants from the NIH under U01HG007019, U01HG007033, U01HG007036, U01HG007037, U41HG006992, U41HG006993, U41HG006994, U41HG006995, U41HG006996, U41HG006997, U41HG006998, U41HG006999, U41HG007000, U41HG007001, U41HG007002, U41HG007003, U54HG006991, U54HG006997, U54HG006998, U54HG007004, U54HG007005, U54HG007010 and UM1HG009442

Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats

Abstract Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer’s disease (AD). While it is known that vascular fibrillar amyloid β (Aβ) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-β1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-β1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses

Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia

Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer’s disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number of cellular responses, including activation of astrocytes and microglia. In addition, fibril structures of the Aβ40 and Aβ42 peptides are known to be polymorphic, which poses a challenge for attributing the contribution of different Aβ sequences and structures to brain pathology. Here, we systematically treated primary astrocytes and microglia with single, well-characterized polymorphs of Aβ40 or Aβ42 fibrils, and performed bulk RNA sequencing to assess cell-specific changes in gene expression. A greater number of genes were up-regulated by Aβ42 fibril-treated glial cells (251 and 2133 genes in astrocyte and microglia, respectively) compared with the Aβ40 fibril-treated glial cells (191 and 251 genes in astrocytes and microglia, respectively). Immunolabeling studies in an AD rat model with parenchymal fibrillar Aβ42 plaques confirmed the expression of PAI-1, MMP9, MMP12, CCL2, and C1r in plaque-associated microglia, and iNOS, GBP2, and C3D in plaque-associated astrocytes, validating markers from the RNA sequence data. In order to better understand these Aβ fibril-induced gene changes, we analyzed gene expression patterns using the Ingenuity pathway analysis program. These analyses further highlighted that Aβ42 fibril treatment up-regulated cellular activation pathways and immune response pathways in glial cells, including IL1β and TNFα in astrocytes, and microglial activation and TGFβ1 in microglia. Further analysis revealed that a number of disease-associated microglial (DAM) genes were surprisingly suppressed in Aβ40 fibril treated microglia. Together, the present findings indicate that Aβ42 fibrils generally show similar, but stronger, stimulating activity of glial cells compared with Aβ40 fibril treatment

Additional file 1 of Cerebrospinal fluid shotgun proteomics identifies distinct proteomic patterns in cerebral amyloid angiopathy rodent models and human patients

Additional file 1: Table S1. shows results of analysis in rTg-DI/WT rodents. Protein characteristics and identifiers are given (Protein.Ids/Gene.Ids/Gene.names/Protein.names). Filter shows which proteins adhered to the filtering step (1 = present in ≥75% of samples of either group; 0 = not present in ≥75% of samples of either group). Results of statistical tests (3M_wcx, 6M_wcx, 12M_wcx, rTg_kw, WT_kw, and all respective variants in which was adjusted for multiple-testing) and fold-changes of medians of rTg-DI/WT are given (3M_FC, 6M_FC, 12M_FC). Signal intensities of individual samples, specified to each respective protein (with increasing age; 3M-6M-12M

Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer\u27s disease

Background: We evaluated the amounts of amyloid beta (Aβ)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Aβ plasma levels and Alzheimer\u27s disease (AD) pathology. Methods: Amyloid β levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects. Results: Plasma Aβ levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Aβ40 than disease-free vessels. Inactivated platelets contained more Aβ peptides than activated ones. Substantially more Aβ was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Aβ. Conclusions: Efforts to use plasma levels of Aβ peptides as AD biomarkers or disease-staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Aβ values is also due in part to the ability of Aβ to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Aβ plasma levels. Furthermore, the long-range impact of Aβ immunotherapy on peripheral Aβ sources should also be considered. © 2009 The Alzheimer\u27s Association