Alzheimer's disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aβ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, Aβ 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 Aβ 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 "typical" APP localization in the Golgi apparatus, with consequences on the Aβ level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and Aβ levels with implications in Alzheimer's disease.

Inhibition of 37/67kDa laminin-1 receptor restores APP maturation and reduces amyloid-β in human skin fibroblasts from familial alzheimer's disease / Antaripa Bhattacharya, Antonella Izzo, Nunzia Mollo, Filomena Napolitano, Adriana Limone, Francesca Margheri, Alessandra Mocali, Giuseppina Minopoli, Alessandra Lo Bianco, Federica Di Maggio, Valeria D'Argenio, Nunzia Montuori, Antonio Lavecchia, Daniela Sarnataro. - In: JOURNAL OF PERSONALIZED MEDICINE. - ISSN 2075-4426. - ELETTRONICO. - 10:(2020), pp. 0-0.

Inhibition of 37/67kDa laminin-1 receptor restores APP maturation and reduces amyloid-β in human skin fibroblasts from familial alzheimer's disease

Antonella Izzo;Francesca Margheri;Alessandra Mocali;
2020

Abstract

Alzheimer's disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aβ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, Aβ 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 Aβ 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 "typical" APP localization in the Golgi apparatus, with consequences on the Aβ level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and Aβ levels with implications in Alzheimer's disease.
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Antaripa Bhattacharya, Antonella Izzo, Nunzia Mollo, Filomena Napolitano, Adriana Limone, Francesca Margheri, Alessandra Mocali, Giuseppina Minopoli, Alessandra Lo Bianco, Federica Di Maggio, Valeria D'Argenio, Nunzia Montuori, Antonio Lavecchia, Daniela Sarnataro
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/1285617
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