1. Cerliponase alfa decreases Aβ load and alters autophagy- related pathways in mouse hippocampal neurons exposed to fAβ 1-42 .
- Author
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Kose S, Cinar E, Akyel H, Cakir-Aktas C, Tel BC, Karatas H, and Kelicen-Ugur P
- Subjects
- Animals, Mice, Signal Transduction drug effects, Sirtuin 1 metabolism, Sirtuin 1 genetics, Aminopeptidases metabolism, Aminopeptidases genetics, Amyloid beta-Peptides metabolism, Autophagy drug effects, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases metabolism, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases genetics, Hippocampus drug effects, Hippocampus metabolism, Neurons drug effects, Neurons metabolism, Peptide Fragments pharmacology, Peptide Fragments metabolism, Serine Proteases metabolism, Tripeptidyl-Peptidase 1
- Abstract
Extracellular aggregation of amyloid-beta (Aβ) in the brain plays a central role in the onset and progression of Alzheimer's disease (AD). Moreover, intraneuronal accumulation of Aβ via oligomer internalization might play an important role in the progression of AD. Deficient autophagy, which is a lysosomal degradation process, occurs during the early stages of AD. Tripeptidyl peptidase-1 (TPP1) functions as a lysosomal enzyme, and TPP1 gene mutations are associated with type 2 late infantile neuronal ceroid lipofuscinosis (LINCL). Nevertheless, there is little information about the role of TPP1 in the pathogenesis of AD; therefore, the present study aimed to measure the decrease in intraneuronal Aβ accumulation by a recombinant analog of the TPP1 enzyme, cerliponase alfa (CER) (Brineura®), and to determine whether autophagy pathways play a role in this decrease. In this study, endogenous Aβ accumulation was induced by fAβ
1-42 (a toxic fragment of full-length Aβ) exposure, and mouse hippocampal neuronal cells (HT-22) were treated with CER (human recombinant rhTPP1 1 mg mL-1 ). Soluble Aβ, TPP1, and the proteins involved in autophagy, including mammalian target of rapamycin (p-mTOR/mTOR), p62/sequestosome-1 (p62/SQSTM1), and microtubule-associated protein 1 A/1B-light chain 3 (LC3), were evaluated using western blotting. The sirtuin-1, beclin-1, and Atg5 genes were also studied using RT-PCR. Aβ and TPP1 localizations were observed via immunocytochemistry. CER reduced the Aβ load in HT-22 cells by inducing TPP1 expression and converting pro-TPP1 into the mature form. Furthermore, exposure to CER and fAβ1-42 induced the autophagy-regulatory/related pathways in HT-22 cells and exposure to CER alone increased sirtuin-1 activity. Based on the present findings, we suggest that augmentation of TPP1 with enzyme replacement therapy may be a potential therapeutic option for the treatment of AD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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