Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/193227
Title: | NMDA receptor antagonists reduce amyloid-β deposition by modulating calpain-1 signaling and autophagy, rescuing cognitive impairment in 5XFAD mice |
Author: | Companys Alemany, Júlia Turcu, Andreea L. Schneider, Marion Müller, Christa E. Vázquez Cruz, Santiago Griñán Ferré, Christian Pallàs i Llibería, Mercè, 1964- |
Keywords: | Malaltia d'Alzheimer Amiloïdosi Alzheimer's disease Amyloidosis |
Issue Date: | 9-Jul-2022 |
Publisher: | Springer Verlag |
Abstract: | Overstimulation of N-methyl-D-aspartate receptors (NMDARs) is the leading cause of brain excitotoxicity and often contributes to neurodegenerative diseases such as Alzheimer's Disease (AD), the most common form of dementia. This study aimed to evaluate a new NMDA receptor antagonist (UB-ALT-EV) and memantine in 6-month-old female 5XFAD mice that were exposed orally to a chronic low-dose treatment. Behavioural and cognitive tests confirmed better cognitive performance in both treated groups. Calcium-dependent protein calpain-1 reduction was found after UB-ALT-EV treatment but not after memantine. Changes in spectrin breakdown products (SBDP) and the p25/p35 ratio confirmed diminished calpain-1 activity. Amyloid β (Aβ) production and deposition was evaluated in 5XFAD mice and demonstrated a robust effect of NMDAR antagonists on reducing Aβ deposition and the number and size of Thioflavin-S positive plaques. Furthermore, glycogen synthase kinase 3β (GSK3β) active form and phosphorylated tau (AT8) levels were diminished after UB-ALT-EV treatment, revealing tau pathology improvement. Because calpain-1 is involved in autophagy activation, autophagic proteins were studied. Strikingly, results showed changes in the protein levels of unc-51-like kinase (ULK1), beclin-1, microtubule-associated protein 1A/1B-light chain 3(LC3B-II)/LC3B-I ratio and lysosomal-associated membrane protein 1 (LAMP1) after NMDAR antagonist treatments, suggesting an accumulation of autophagolysosomes in 5XFAD mice, reversed by UB-ALT-EV. Likewise, treatment with UB-ALT-EV recovered a WT mice profile in apoptosis markers Bcl-2, Bax, and caspase-3. In conclusion, our results revealed the potential neuroprotective effect of UB-ALT-EV by attenuating NMDA-mediated apoptosis and reducing Aβ deposition and deposition jointly with the autophagy rescue to finally reduce cognitive alterations in a mice model of familial AD. |
Note: | Reproducció del document publicat a: https://doi.org/10.1007/s00018-022-04438-4 |
It is part of: | Cellular and Molecular Life Sciences, 2022, vol. 79, num. 8, p. 408 |
URI: | http://hdl.handle.net/2445/193227 |
Related resource: | https://doi.org/10.1007/s00018-022-04438-4 |
ISSN: | 1420-682X |
Appears in Collections: | Articles publicats en revistes (Institut de Biomedicina (IBUB)) Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
724540.pdf | 3.89 MB | Adobe PDF | View/Open |
This item is licensed under a
Creative Commons License