Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10636 (tau protein)
 5,110 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seladin-1 is a gene recently shown to be down-regulated in brain regions selectively degenerated in Alzheimer's disease. The sequence of seladin-1 shares similarities with flavin-adenine-dinucleotide-dependent oxidoreductases and it has been found to protect cells from apoptotic cell death. In this work, we show that the transcription of seladin-1 is selectively down-regulated in the brain areas affected in Alzheimer's disease. The down-regulation in seladin-1 transcription was associated with hyperphosphorylated tau seen as linkage to immunohistochemically detected paired helical filament tau, neuritic plaques and neurofibrillary tangles. In contrast, no association was found between seladin-1 transcription and beta-amyloid deposition when analyzing human samples or tissue from transgenic animals. Furthermore, the relative transcription of seladin-1 was found to fluctuate during aging in the transgenic mouse model of Alzheimer's disease. The fluctuation was enhanced by Alzheimer's disease causing mutations in presenilin-1 and amyloid precursor protein genes. Finally, seladin-1 transcription was found to be up-regulated in mouse N2a cells induced to undergo apoptosis with okadaic acid. The results presented here indicate that seladin-1 transcription is selectively down-regulated in brain regions vulnerable to Alzheimer's disease and this down-regulation is associated with the hyperphosphorylation of tau protein.
 ...
PMID:Seladin-1 transcription is linked to neuronal degeneration in Alzheimer's disease. 1212 87

The products of the Herpes simplex (HSV-1) genome interact with many Alzheimer's disease susceptibility genes or proteins. These in turn affect those of the virus. For example, HSV-1 binds to heparan sulphate proteoglycans (HSPG2), or alpha-2-macroglobulin (A2M), and enters cells via nectin receptors, which are cleaved by gamma-secretase (APH1B, PSEN1, PSEN2, PEN2, NCSTN). The virus also binds to blood-borne lipoproteins and apolipoprotein E (APOE) is able to modify its infectivity. Viral uptake is cholesterol- and lipid raft-dependent (DHCR24, HMGCR, FDPS, RAFTLIN, SREBF1). The virus is transported to the nucleus via the dynein and kinesin (KNS2) motors associated with the microtubule network (MAPT). Amyloid precursor protein (APP) plays a role in this transport. Nuclear export is mediated via disruption of the nuclear lamina and binding to LMNA. Herpes simplex activates kinases (CDC2 and casein kinase 2) whose substrates include APOE, APP, MAPT, PSEN2, and SREBF1. A viral protein is also able to delete mitochondrial DNA, a situation prevalent in Alzheimer's disease. The virus binds to the host transcription factors transcription factor CP2 (TFCP2) and POU2F1 that control many other genes associated with Alzheimer's disease. Viral latency is controlled by IL6 and IL1B and at different stages of its life cycle the virus can either promote or attenuate apoptosis via Fas and tumor necrosis factor pathways (FAS, TNF, DAPK1, PARP1). Viral evasion strategies include inhibition of the antigen processor TAP2, the production of an Fc immunoglobulin receptor mimic (FCER1G) and inhibition of the viral-activated kinase EIF2AK2. These and other host/viral interactions, targeted to certain Alzheimer's disease susceptibility genes, support the idea that some form of synergy between the pathogen and genetic factors may play a role in the pathology of late-onset Alzheimer's disease.
 ...
PMID:Interactions between the products of the Herpes simplex genome and Alzheimer's disease susceptibility genes: relevance to pathological-signalling cascades. 1816 3

Involvement of life stress in Late-Onset Alzheimer's Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.
 ...
PMID:Early Life Stress and Epigenetics in Late-onset Alzheimer's Dementia: A Systematic Review. 3038 71