Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-β in Human Skin Fibroblasts from Familial Alzheimer’s Disease
| Autor: | Filomena Napolitano, Federica Di Maggio, Francesca Margheri, Alessandra Mocali, Nunzia Mollo, Giuseppina Minopoli, Daniela Sarnataro, Antaripa Bhattacharya, Valeria D'Argenio, Antonella Izzo, Antonio Lavecchia, Alessandra Lo Bianco, Nunzia Montuori, Adriana Limone |
|---|---|
| Přispěvatelé: | Bhattacharya, Antaripa, Izzo, Antonella, Mollo, Nunzia, Napolitano, Filomena, Limone, Adriana, Margheri, Francesca, Mocali, Alessandra, Minopoli, Giuseppina, Lo Bianco, Alessandra, Di Maggio, Federica, D'Argenio, Valeria, Montuori, Nunzia, Lavecchia, Antonio, Sarnataro, Daniela |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Gene isoform
Amyloid beta Medicine (miscellaneous) amyloid-β Article 03 medical and health sciences symbols.namesake 0302 clinical medicine Laminin mental disorders Amyloid precursor protein Receptor 37/67kDa laminin-1 receptor inhibitor 030304 developmental biology 0303 health sciences biology Chemistry Golgi apparatus Cell biology amyloid precursor protein APP Cell culture biology.protein symbols Alzheimer’s disease 030217 neurology & neurosurgery Intracellular NSC47924 |
| Zdroj: | Journal of Personalized Medicine Volume 10 Issue 4 |
| ISSN: | 2075-4426 |
| DOI: | 10.3390/jpm10040232 |
| Popis: | Alzheimer&rsquo s disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (A&beta ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and &gamma secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, A&beta and 37/67kDa laminin receptor (LR), finding the possibility to regulate intracellular APP localization and maturation through modulation of the receptor. Here, we report that in fibroblasts from familial AD (fAD), APP was prevalently expressed as an immature isoform and accumulated preferentially in the transferrin-positive recycling compartment rather than in the Golgi apparatus. Moreover, besides the altered mitochondrial network exhibited by fAD patient cells, the levels of pAkt and pGSK3 were reduced in respect to healthy control fibroblasts and were accompanied by an increased amount of secreted A&beta in conditioned medium from cell cultures. Interestingly, these features were reversed by inhibition of 37/67kDa LR by NSC47924 a small molecule that was able to rescue the &ldquo typical&rdquo APP localization in the Golgi apparatus, with consequences on the A&beta level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and A&beta levels with implications in Alzheimer&rsquo s disease. |
| Databáze: | OpenAIRE |
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