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Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-? in Human Skin Fibroblasts from Familial Alzheimer's Disease.


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

SUBMITTER: Bhattacharya A 

PROVIDER: S-EPMC7712490 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-β in Human Skin Fibroblasts from Familial Alzheimer's Disease.

Bhattacharya Antaripa A   Izzo Antonella A   Mollo Nunzia N   Napolitano Filomena F   Limone Adriana A   Margheri Francesca F   Mocali Alessandra A   Minopoli Giuseppina G   Lo Bianco Alessandra A   Di Maggio Federica F   D'Argenio Valeria V   Montuori Nunzia N   Lavecchia Antonio A   Sarnataro Daniela D  

Journal of personalized medicine 20201116 4


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 lo  ...[more]

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