Cerliponase alfa decreases Aß load and alters autophagy- related pathways in mouse hippocampal neurons exposed to fAß1-42.
Life Sci
; 357: 123105, 2024 Oct 01.
Article
in En
| MEDLINE
| ID: mdl-39362589
ABSTRACT
Extracellular aggregation of amyloid-beta (Aß) in the brain plays a central role in the onset and progression of Alzheimer's disease (AD). Moreover, intraneuronal accumulation of Aß 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 Aß 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 Aß accumulation was induced by fAß1-42 (a toxic fragment of full-length Aß) exposure, and mouse hippocampal neuronal cells (HT-22) were treated with CER (human recombinant rhTPP1 1 mg mL-1). Soluble Aß, 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. Aß and TPP1 localizations were observed via immunocytochemistry. CER reduced the Aß load in HT-22 cells by inducing TPP1 expression and converting pro-TPP1 into the mature form. Furthermore, exposure to CER and fAß1-42 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.
Full text:
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Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Life Sci
Year:
2024
Document type:
Article
Country of publication:
Netherlands