1.
Vitamin D concentration and risk of Alzheimer disease: A meta-analysis of prospective cohort studies.
Yang, K, Chen, J, Li, X, Zhou, Y
Medicine. 2019;(35):e16804
-
-
Free full text
-
Abstract
BACKGROUND Considerable controversy exists on the association between serum vitamin D concentrations and Alzheimer disease (AD) risk. This study aimed to synthesize the association of serum vitamin D concentrations with AD in adults. METHODS PubMed, Embase, and Cochrane library databases were searched for prospective cohort studies with data on serum vitamin D concentrations and AD risk. RESULT The studies that reported the adjusted relative risks (RRs) with 95% confidence intervals (CIs) of AD associated with serum vitamin D concentrations were included and subjected to subgroup analyses. Six prospective cohort studies with 1607 AD cases and 21,692 individuals were included in the meta-analysis. In 4 cohort studies with information about serum vitamin D concentrations <25 and 25 to 50 nmol/L, the random effects summary estimate did not show an increased risk of AD after adjustment for the established risk factors, while 3 cohort studies reported the RRs for incident AD per standard deviation (SD) decrease in serum vitamin D concentration and the random effects summary estimate did not show an increased risk of AD after adjustment for the established risk factors. CONCLUSIONS The current meta-analysis indicated that serum vitamin D deficiency (<25 nmol/L) or insufficiency (25-50 nmol/L) was not statistically significant and associated with the risk of AD.
2.
Integrated genomic approaches identify major pathways and upstream regulators in late onset Alzheimer's disease.
Li, X, Long, J, He, T, Belshaw, R, Scott, J
Scientific reports. 2015;:12393
Abstract
Previous studies have evaluated gene expression in Alzheimer's disease (AD) brains to identify mechanistic processes, but have been limited by the size of the datasets studied. Here we have implemented a novel meta-analysis approach to identify differentially expressed genes (DEGs) in published datasets comprising 450 late onset AD (LOAD) brains and 212 controls. We found 3124 DEGs, many of which were highly correlated with Braak stage and cerebral atrophy. Pathway Analysis revealed the most perturbed pathways to be (a) nitric oxide and reactive oxygen species in macrophages (NOROS), (b) NFkB and (c) mitochondrial dysfunction. NOROS was also up-regulated, and mitochondrial dysfunction down-regulated, in healthy ageing subjects. Upstream regulator analysis predicted the TLR4 ligands, STAT3 and NFKBIA, for activated pathways and RICTOR for mitochondrial genes. Protein-protein interaction network analysis emphasised the role of NFKB; identified a key interaction of CLU with complement; and linked TYROBP, TREM2 and DOK3 to modulation of LPS signalling through TLR4 and to phosphatidylinositol metabolism. We suggest that NEUROD6, ZCCHC17, PPEF1 and MANBAL are potentially implicated in LOAD, with predicted links to calcium signalling and protein mannosylation. Our study demonstrates a highly injurious combination of TLR4-mediated NFKB signalling, NOROS inflammatory pathway activation, and mitochondrial dysfunction in LOAD.
3.
Structure-activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease.
Li, X, Hong, L, Coughlan, K, Wang, L, Cao, L, Tang, J
Acta biochimica et biophysica Sinica. 2013;(8):613-21
-
-
Free full text
-
Abstract
Memapsin 2 (BACE1, β-secretase), a membrane aspartic protease, functions in the cleavage of the type I transmembrane protein, β-amyloid precursor protein (APP), leading to the production of amyloid β (Aβ) in the brain. Since Aβ is closely associated with the pathogenesis of Alzheimer's disease, understanding the biological function, particularly the catalytic activities of memapsin 2, would assist in a better understanding of the disease and the development of its inhibitors. The transmembrane and cytosolic domains of memapsin 2 function in cellular transport and localization, which are important regulatory mechanisms for its activity. The catalytic ectodomain contains a long substrate cleft that is responsible for substrate recognition, specificity, and peptide bond hydrolysis. The substrate cleft accommodates 11 residues of the substrate in separate binding subsites. Besides APP, a number of membrane proteins have been reported to be substrates of memapsin 2. The elucidation for the specificity of these subsites and the amino acid sequences surrounding the memapsin 2 cleavage site in these proteins has led to the establishment of a predictive model that can quantitatively estimate the efficiency of cleavage for any potential substrates. Such tools may be employed for future studies of memapsin 2 about its biological function. Herein, we review the current knowledge on the structure-function relationship of memapsin 2 and its relationship in the biological function.