Jacome, D. | Search bioRxiv

bioRxiv2026

cis-gamma-Amino-L-proline peptides as chemical probes of amyloidogenic processing in neurons and APP/PS1 mice

Alzheimers disease (AD) is characterized by the accumulation of amyloid-{beta} (A{beta}) peptides, which are a key factor in its pathogenesis. In this study, we present the design and evaluation of {gamma}-amino-L-proline peptides as metabolically stable, cell-penetrating molecules that can modulate amyloidogenic processing. We screened a library of {gamma}-peptides in primary neuronal cultures to determine their effects on endogenous A{beta}1-42 production, cytotoxicity, and {beta}-secretase (BACE1) activity. Comparative analysis of structurally related analogues enabled the identification of molecular features associated with A{beta}-lowering activity, establishing a qualitative structure-activity relationship. Peptide 33 (P33) emerged as a lead candidate, selectively reducing BACE1 activity without significantly inhibiting the homologous enzyme, BACE2. In vitro blood-brain barrier (BBB) assays revealed that P33 exhibits favorable transendothelial permeability. Intraperitoneal administration of P33 in APP/PS1 mice decreased A{beta} levels, reduced amyloid plaque burden, and improved performance in a behavioral recognition task without inducing cytotoxicity or systemic toxicity. These results define cis-{gamma}-amino-L-proline peptides as a bioorganically distinct and modular scaffold for the development of intracellular modulators of A{beta} production. HighlightsO_LI{gamma}LJAminoLJLLJproline peptides as metabolically stable modulators of A{beta} production. C_LIO_LIP33 showed BBB permeability and BACE1 inhibition in primary cortical neurons. C_LIO_LIIn APP/PS1 mice, P33 lowers amyloid burden and improves cognition. C_LIO_LIP33 shows good biocompatibility, supporting its therapeutic potential in AD C_LI

neuroscience↗

bioRxiv2023

miR-519a-3p, found to regulate cellular prion protein during Alzheimer's disease pathogenesis, as a biomarker of asymptomatic stages

MiRNAs induce post-transcriptional gene silencing by binding to the 3-UTR of complementary messenger RNAs and causing either degradation or inhibition of translation. The clinical relevance of miRNAs as biomarkers is growing due to their stability and detection in biofluids. In this sense, diagnosis at asymptomatic stages of Alzheimers disease (AD) remains a challenge since it can only be made at autopsy according to Braak NFT staging. Achieving the objective of detecting AD at early stages would allow possible therapies to be addressed before the onset of cognitive impairment. Many studies have determined that the expression pattern of some miRNAs is deregulated in AD patients, but to date, none has been correlated with downregulated expression of cellular prion protein (PrPC) during disease progression. That is why, by means of cross studies of miRNAs up-regulated in AD with in silico identification of potential miRNAs-binding to 3UTR of human PRNP gene, we selected miR-519a-3p for our study. Other family members of miR-519 have been shown to bind to the 3UTR region of PRNP in vitro and presumably degrade PRNP mRNA. In addition, up-regulation of some of them has been reported in various tissues from AD patients, including cerebrospinal fluid, plasma, and blood serum. In fact, miR-519d-3p is marked as a bridge regulator between mild cognitive impairment and severe AD. However, none of the studies address the prodromal stages of the disease or the expression profile of miR-519 in other neurodegenerative diseases that also may present dementia. Therefore, in this study we analyzed miR-519a-3p expression in cerebral samples of AD at different stages of evolution as well as other neurodegenerative diseases such as other tauopathies and synucleinopathies. Our results show the specific and early upregulation of miR-519a-3p starting from Braak stage I of AD, suggesting its potential use as a biomarker of preclinical stages of the disease.

neuroscience↗