NMDA receptor antagonists reduce amyloid-β deposition by modulating calpain-1 signaling and autophagy, rescuing cognitive impairment in 5XFAD mice

Companys-Alemany, J.; Turcu, A. L.; Schneider, M.; Müller, C. E.; Vázquez, S.; Griñán-Ferré, C.; Pallàs, M.  Cell Mol Life Sci. 2022, doi: 10.1007/s00018-022-04438-4.

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. Behavioral 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 (ULK-1), beclin-1, microtubule-associated protein 1A/1B-light chain 3(LC3B-II)/LC3B-I ratio, and lysosomal-associated membrane protein 1 (LAMP-1) 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.

Unveiling the multitarget anti-Alzheimer drug discovery landscape: A bibliometric analysis

Sampietro, A.; Pérez-Areales, F. J.; Martínez, P.; Arce, E. M.; Galdeano, C.; Muñoz-Torrero, D. Pharmaceuticals 2022, 15, 545

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Discovery and in vivo proof of concept of a highly potent dual inhibitor of soluble epoxide hydrolase and acetylcholinesterase for the treatment of Alzheimer’s disease

Codony, S.; Pont, C.; Griñán-Ferré, C.; Di Pede-Mattatelli, A.; Calvó-Tusell, C.; Feixas, F.; Osuna, S.; Jarné-Ferrer, J.; Naldi, M.; Bartolini,…

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Disease-modifying treatment with I 2 imidazoline receptor ligand LSL60101 in an Alzheimer’s disease mouse model: a comparative study with donepezil

Vasilopoulou F, Rodríguez-Arévalo S, Bagán A, Escolano C, Griñán-Ferré C, Pallàs M. Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in…

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Inhibition of Soluble Epoxide Hydrolase Ameliorates Phenotype and Cognitive Abilities in a Murine Model of Niemann Pick Type C Disease

Griñán-Ferré C, Companys-Alemany J, Jarné-Ferrer J, Codony S, González-Castillo C, Ortuño-Sahagún D, Vilageliu L, Grinberg D, Vázquez S, Pallàs M.…

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A Novel NMDA Receptor Antagonist Protects against Cognitive Decline Presented by Senescent Mice.

Companys-Alemany J, Turcu AL, Bellver-Sanchis A, Loza MI, Brea JM, Canudas AM, Leiva R, Vázquez S, Pallàs M, Griñán-Ferré C.Pharmaceutics. 2020. 12(3). pii: E284. doi: 10.3390/pharmaceutics12030284. https://www.mdpi.com/1999-4923/12/3/284/htm

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