Bhattacharya, Antaripa (2020) The role of the 37kDa/67kDa LR inhibitor in Amyloid precursor protein trafficking and Alzheimer’s disease. [Tesi di dottorato]


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Item Type: Tesi di dottorato
Resource language: English
Title: The role of the 37kDa/67kDa LR inhibitor in Amyloid precursor protein trafficking and Alzheimer’s disease
Date: March 2020
Number of Pages: 84
Institution: Università degli Studi di Napoli Federico II
Department: Medicina Molecolare e Biotecnologie Mediche
Dottorato: Medicina molecolare e biotecnologie mediche
Ciclo di dottorato: 32
Coordinatore del Corso di dottorato:
Avvedimento, Vittorio
Sarnataro, DanielaUNSPECIFIED
Date: March 2020
Number of Pages: 84
Keywords: Alzheimer's disease; 37/67 kDa laminin receptor; Amyloid precursor protein (APP); intracellular trafficking; posttranslational modifications; prion; small molecule inhibitors.
Settori scientifico-disciplinari del MIUR: Area 05 - Scienze biologiche > BIO/12 - Biochimica clinica e biologia molecolare clinica
Area 05 - Scienze biologiche > BIO/13 - Biologia applicata
Additional information: NA
Date Deposited: 25 Mar 2020 11:46
Last Modified: 08 Nov 2021 12:11

Collection description

The vicious circle of spread, seed, and accumulation of misfolded protein aggregates within the central nervous system has been reported for prion protein, but also amyloid beta-peptide (Aβ), α-synuclein and tau, which can form amyloidogenic aggregates that spread through the brain causing distinct neurodegenerative diseases. Amyloid precursor protein (APP) is processed along both the non-amyloidogenic pathway preventing Aβ production and the amyloidogenic pathway, generating Aβ, whose accumulation in the brain is a neuropathological hallmark of Alzheimer’s disease. The A is produced by the sequential processing of APP by β- and γ-secretases likely in the endo/lysosomal pathway where APP physiologically traffics and where γ-secretases are preferentially distributed. Items of evidence report that the intracellular trafficking plays a key role in the generation of Aβ and that the 37/67kDa laminin receptor LR, acting as a receptor for Aβ, may mediate Aβ-pathogenicity. Although many reports suggest a critical role for intracellular trafficking of APP in Aβ generation, little is known on the exact site for Aβ production, its localization and the possibility to correct them for proper protein folding and function. Mutations in APP cleavage sites and in the Aβ sequence can affect the processing of the protein with consequences in the trafficking, folding, posttranslational modifications (PTMs: glycosylation, phosphorylation, acetylation) and amyloidogenic abilities. Therapeutics for misfolding disorders do not exist. Previous reports revealing a critical role for 37/67kDa laminin receptor in APP processing through direct interaction with the γ-secretases and indirect with β-secretase, highlight the importance of identifying therapeutics that point to target the 37/67kDa LR, which has been previously shown by us to be also interactor and regulator of prion protein trafficking. Starting from these observations, we propose to shed light on the role of 37/67kDa LR in APP processing and trafficking by assaying the effects of receptor inhibitors in neuronal cells and fibroblasts from AD patients challenged with different molecules already tested to be receptor inhibitors. We show herein that APP and 37/67Kda LR interact in neuronal cells and that the specific 37/67kDa LR inhibitor, NSC48478, can affect this interaction. Moreover, NSC48478 reversibly regulates the maturation of APP, in an NH4Cl-dependent manner, resulting in the partial accumulation of the immature APP isoforms (unglycosylated/acetylated forms) in both the Endoplasmic Reticulum and Transferrin-positive recycling endosomes, indicating alteration of the APP intracellular trafficking. By shRNA-mediated knockdown of the receptor, we found that these effects were directly mediated by the 37/67kDa LR and accompanied by inactivation of ERK1/2 signaling and activation of Akt, with concomitant inactivation of GSK3β. Our data reveal NSC48478 inhibitor as a novel small compound to be tested in disease conditions. Our data reveal a different localization of APP in fibroblasts of AD patients compared to control fibroblasts, and while NSC48478 did not exert any effect on APP localization, the analog small molecule NSC47924 was able to rescue the physiological Golgi distribution of APP in AD-patient fibroblasts. These data reveal that the small 37/67kDa LR inhibitors are useful tools to be tested against AD.


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