| First Author | Eckman EA | Year | 2023 |
| Journal | J Neurosci | Volume | 43 |
| Issue | 50 | Pages | 8812-8824 |
| PubMed ID | 37884349 | Mgi Jnum | J:355536 |
| Mgi Id | MGI:7719135 | Doi | 10.1523/JNEUROSCI.1318-23.2023 |
| Citation | Eckman EA, et al. (2023) Nascent Abeta42 Fibrillization in Synaptic Endosomes Precedes Plaque Formation in a Mouse Model of Alzheimer's-like beta-Amyloidosis. J Neurosci 43(50):8812-8824 |
| abstractText | Accumulation of amyloid-beta peptide (Abeta) aggregates in synapses may contribute to the profound synaptic loss characteristic of Alzheimer's disease (AD). The origin of synaptic Abeta aggregates remains elusive, but loss of endosomal proteostasis may trigger their formation. In this study, we identified the synaptic compartments where Abeta accumulates, and performed a longitudinal analysis of synaptosomes isolated from brains of TgCRND8 APP transgenic mice of either sex. To evaluate the specific contribution of Abeta-degrading protease endothelin-converting enzyme (ECE-1) to synaptic/endosomal Abeta homeostasis, we analyzed the effect of partial Ece1 KO in brain and complete ECE1 KO in SH-SY5Y cells. Global inhibition of ECE family members was used to further assess their role in preventing synaptic Abeta accumulation. Results showed that, before extracellular amyloid deposition, synapses were burdened with detergent-soluble Abeta monomers, oligomers, and fibrils. Levels of all soluble Abeta species declined thereafter, as Abeta42 turned progressively insoluble and accumulated in Abeta-producing synaptic endosomal vesicles with characteristics of multivesicular bodies. Accordingly, fibrillar Abeta was detected in brain exosomes. ECE-1-deficient mice had significantly increased endogenous synaptosomal Abeta42 levels, and protease inhibitor experiments showed that, in TgCRND8 mice, synaptic Abeta42 became nearly resistant to degradation by ECE-related proteases. Our study supports that Abeta accumulating in synapses is produced locally, within endosomes, and does not require the presence of amyloid plaques. ECE-1 is a determinant factor controlling the accumulation and fibrillization of nascent Abeta in endosomes and, in TgCRND8 mice, Abeta overproduction causes rapid loss of Abeta42 solubility that curtails ECE-mediated degradation.SIGNIFICANCE STATEMENT Deposition of aggregated Abeta in extracellular plaques is a defining feature of AD. Abeta aggregates also accumulate in synapses and may contribute to the profound synaptic loss and cognitive dysfunction typical of the disease. However, it is not clear whether synaptotoxic Abeta is mainly derived from plaques or if it is produced and aggregated locally, within affected synaptic compartments. Filling this knowledge gap is important for the development of an effective treatment for AD, as extracellular and intrasynaptic pools of Abeta may not be equally modulated by immunotherapies or other therapeutic approaches. In this manuscript, we provide evidence that Abeta aggregates building up in synapses are formed locally, within synaptic endosomes, because of disruptions in nascent Abeta proteostasis. |
