Modeling endophilin-mediated Aβ disposal in glioma cells

Abstract

Autophagy dysregulation has emerged in age-related neurological diseases (Ulland et al.; Matheoud et al.; Ashkenazi et al.). Alzheimer Disease (AD), the most common progressive neurodegenerative disorder, is characterized by the accumulation of amyloid-β (Aβ) plaques caused by aberrant Aβ metabolism (Qiang et al.; Sevigny et al.; Ittner et al.). Glia constitute the brain immune system and ingest extracellular Aβ for degradation via the autophagy-lysosome machinery (Ries and Sastre; Cho et al.). Here, we model the molecular rationale for this clearance process in glioma cells by showing that miR34a inhibits autophagy-mediated disposal of Aβ fibrils and identifying two novel direct targets of miR34a, endophilin-3 and cathepsin B (CTSB, a previously reported enzyme for Aβ degrading (Sun et al.)). Bioinformatics analyses revealed that endophilin-3 expresses at a significantly lower level in neurodegenerative diseases. Its gain-of-function substantially promotes both uptake and degradation of Aβ while small interfering RNA (siRNA)-mediated endophilin-3 knockdown slowed down Aβ clearance and blocked autolysosome formation. Mechanistically, gene ontology (GO) analysis of the endophilin-3 interactome identified by mass spectrometry uncovered enriched components involved in actin binding (with the highest score). Importantly, we validated that the actin-binding protein phostensin interacted with endophilin-3. Phostensin knockdown restored endophilin-3-mediated up-regulation of Aβ clearance. Thus, our findings indicate that miR34a inhibits Aβ clearance by targeting endophilin-3 and CTSB at multiple steps including uptake and autophagy-mediated degradation.

Chronic Periodontitis and Alzheimer Disease: A Putative Link of Serum Proteins Identification by 2D-DIGE Proteomics

“…Evidence also indicates that Cathepsin B has β-secretase activity, participating in APP-processing and cutting to Aβ (Perlenfein and Murphy, 2017;Batkulwar et al, 2018;Sun et al, 2018). Therefore, the molecular mechanism of Cathepsin B in the pathology of AD is interesting.…”

Unscheduled epigenetic modifications cause genome instability and sterility through aberrant R-loops following starvation

“…Peaks were called using MACS software ( 22 ) and were annotated with HOMER using RefSeq annotations. Gene ontology and genome ontology analyses are also performed at this stage by DAVID functional annotation bioinformatics microarray analysis https://david.ncifcrf.gov ( 23 ). De novo motif analyses were also performed with HOMER.…”

miRNA Alterations Elicit Pathways Involved in Memory Decline and Synaptic Function in the Hippocampus of Aged Tg4-42 Mice

“…MiR-345-5p may act as blood biomarker in multiple sclerosis (Freiesleben et al, 2016), and miR-345-3p attenuated apoptosis and inflammation caused by oxidized low-density lipoprotein by targeting TRAF6 via TAK1/p38/NF-kB signaling (Wei et al, 2020). An in vitro study indicated that miR-34a may inhibit Aβ clearance by targeting endophilin-3 including uptake and autophagy-mediated degradation (Sun et al, 2018). The rs1050283 SNP likely acts as a risk factor for sporadic AD.…”