Gemfibrozil, an agonist of PPARα, induced the recruitment of PPARα:retinoid x receptor α, but not PPARγ coactivator 1α (PGC1α), to the Adam10 promoter in wild-type mouse hippocampal neurons and shifted APP processing toward the α-secretase, as determined by augmented soluble APPα and decreased Aβ production.
In addition, our data verified that YXQN decreased the cerebral amyloid load by attenuating β-secretase BACE1 and γ-secretase PS1 in the pathological processing of APP, and promoting the level of α-secretase ADAM10 in the physiological processing of APP to generate more sAPPα, which combats amyloidosis formation, and also carries out neurotropic and neuroprotective effect.
Similarly, transgenic ADAM10 endothelial knockout mice displayed lower LRP1 shedding in the brain and significantly enhanced Aβ clearance across the BBB compared to wild-type animals.
This age-dependent shift in Aβ peptide profile coincided with reduced expression of glycosylated species of ADAM-10 (α-secretase) and BACE1 (β-secretase), and an increased co-immunoprecipitation of presenilin-1 with nicastrin (components of the γ-secretase complex).
We observed an increase in ADAM10 and a decrease in BACE1 and APP695 protein levels and, subsequently, a reduction in Aβ levels and Aβ burden were present in HupA-treated mouse brain, suggesting that HupA enhances the nonamyloidogenic APP cleavage pathway.
Focusing on the donor's sex and APOE ε4 status as nominal variables (i.e., omitting diagnosis from the stratification) revealed that increases in Aβ peptides were specific to female carriers of the ε4 allele and correlated with the proportional expression of BACE1/β-secretase and ADAM10/α-secretase in the cortex and with nicastrin (γ-secretase) expression in the hippocampus.
Adiponectin values were a significant predictor for amyloidosis (AUC 0.75, 95 CI: 0.56-0.94, p<0.03), with a predicting cut-off value set at 23.16 pg/ml, the predictive positive value was 53.8%.
Moreover, we found that Acrp 30 attenuated the apoptosis and the tight junction disruption through AdipoR1-mediated NF-κB pathway in Aβ-exposed bEnd.3 cells.
Moreover, we found that Acrp 30 attenuated the apoptosis and the tight junction disruption through AdipoR1-mediated NF-κB pathway in Aβ-exposed bEnd.3 cells.
Abbreviations β<sub>2</sub>m β<sub>2</sub>-microglobulin 3D three dimensional AD Alzheimer's disease ADT AutoDock Tools DRA Dialysis-related amyloidosis DSSP dictionary of secondary structure of proteins FEL free energy landscape GROMACS GROningen MAchine for Chemical Simulations LGA Lamarckian Genetic Algorithm LINCS LINear Constraint Solver MC main chain MD molecular dynamics MHC-I major histocompatibility complex class I MM-PBSA molecular mechanics Poisson-Boltzmann surface area PME nanometer (nm); particle mesh ewald PCA principal component analysis PDB protein data bank <i>R</i><sub>g</sub> radius-of-gyration RSV rifamycin SV RMSD root-mean-square deviation RMSF root-mean-square fluctuation SC side chain SPC simple point charge SASA Solvent accessible surface area VMD visual molecular dynamics Communicated by Ramaswamy H. Sarma.
Using immunohistochemistry, AGEs, CML, and RAGE were found within amyloid deposits, more commonly in AA amyloid than in AL amyloid and not in ATTR amyloid.
Our results demonstrate a prominent role for the RAGE-dependent neuroinflammatory pathway in the synaptic failure induced by Aβ and triggered by transient ischemia.
Additionally, following apical exposure to the BBB model, we found that apoE4 bound to Aβ is able to penetrate the BBB more readily than apoE3 bound to Aβ and does so via the RAGE (receptor for advanced glycation end products) transporter.
In conclusion, TXL improved cognition and decreased Aβ in SHRs in a dose- and time-dependent manner, the underlying mechanism may involved in inhibiting RAGE and β-secretase expression.
The results showed that long-term consumption of alcohol aggravated cognitive decline, increased the permeability of the BBB, led to pathomorphological changes and downregulated some related structural proteins (zonula occludens-1, VE-cadherin, and occludin) and functional proteins (major facilitator superfamily domain-containing protein-2a (Mfsd2a), low-density lipoprotein receptor-related protein-1 (LRP1), receptor for advanced glycation end products (RAGE), and aquaporin-4 (AQP4)) in the BBB but did not increase the concentration of Aβ<sub>1-42</sub>.
One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes, at sites of oxidant stress in tissues, and in renal failure and amyloidoses.
Our results showed that Acrp30 (a globular form of adiponectin) reduces the expression of proinflammatory cytokines and the expression of RAGE as Aβ transporters into brain.
Moreover, we show that all RAGE fragments apart from the shortest one (60-62), were able to protect neuronal primary cultures from amyloid toxicity, by preventing the caspase 3 activation induced by Aβ 1-42.
Our results support the involvement of the EC in the development and progression of the synaptic and behavioural deficit during amyloid-dependent neurodegeneration and demonstrate that microglial RAGE activation in presence of Aβ-enriched environment contributes to the EC vulnerability.