| First Author | Wirth S | Year | 2024 |
| Journal | Glia | Volume | 72 |
| Issue | 8 | Pages | 1451-1468 |
| PubMed ID | 38629411 | Mgi Jnum | J:350286 |
| Mgi Id | MGI:7662735 | Doi | 10.1002/glia.24539 |
| Citation | Wirth S, et al. (2024) Astrocytic uptake of posttranslationally modified amyloid-beta leads to endolysosomal system disruption and induction of pro-inflammatory signaling. Glia 72(8):1451-1468 |
| abstractText | The disruption of astrocytic catabolic processes contributes to the impairment of amyloid-beta (Abeta) clearance, neuroinflammatory signaling, and the loss of synaptic contacts in late-onset Alzheimer's disease (AD). While it is known that the posttranslational modifications of Abeta have significant implications on biophysical properties of the peptides, their consequences for clearance impairment are not well understood. It was previously shown that N-terminally pyroglutamylated Abeta3(pE)-42, a significant constituent of amyloid plaques, is efficiently taken up by astrocytes, leading to the release of pro-inflammatory cytokine tumor necrosis factor alpha and synapse loss. Here we report that Abeta3(pE)-42, but not Abeta1-42, gradually accumulates within the astrocytic endolysosomal system, disrupting this catabolic pathway and inducing the formation of heteromorphous vacuoles. This accumulation alters lysosomal kinetics, lysosome-dependent calcium signaling, and upregulates the lysosomal stress response. These changes correlate with the upregulation of glial fibrillary acidic protein (GFAP) and increased activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB). Treatment with a lysosomal protease inhibitor, E-64, rescues GFAP upregulation, NF-kappaB activation, and synapse loss, indicating that abnormal lysosomal protease activity is upstream of pro-inflammatory signaling and related synapse loss. Collectively, our data suggest that Abeta3(pE)-42-induced disruption of the astrocytic endolysosomal system leads to cytoplasmic leakage of lysosomal proteases, promoting pro-inflammatory signaling and synapse loss, hallmarks of AD-pathology. |
