A PHP Error was encountered

Severity: Warning

Message: file_get_contents(https://...@pubfacts.com&api_key=b8daa3ad693db53b1410957c26c9a51b4908&a=1): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests

Filename: helpers/my_audit_helper.php

Line Number: 176

Backtrace:

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 176
Function: file_get_contents

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 250
Function: simplexml_load_file_from_url

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 1034
Function: getPubMedXML

File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3152
Function: GetPubMedArticleOutput_2016

File: /var/www/html/application/controllers/Detail.php
Line: 575
Function: pubMedSearch_Global

File: /var/www/html/application/controllers/Detail.php
Line: 489
Function: pubMedGetRelatedKeyword

File: /var/www/html/index.php
Line: 316
Function: require_once

Targeting the APP-Mint2 Protein-Protein Interaction with a Peptide-Based Inhibitor Reduces Amyloid-β Formation. | LitMetric

AI Article Synopsis

  • - There is a critical need for new treatments for Alzheimer's disease (AD) that can relieve symptoms and slow progression, particularly targeting the harmful accumulation of amyloid-β (Aβ) peptides, which arise from the amyloid precursor protein (APP).
  • - Previous research on Mint2, a protein that interacts with APP and the enzyme complex responsible for Aβ production, has shown mixed results on whether it promotes or inhibits Aβ generation.
  • - This study clarifies that Mint2 facilitates Aβ formation and highlights a promising therapeutic strategy by using a stable peptide inhibitor to target the APP-Mint2 interaction, which could significantly lower Aβ levels in neuronal models of AD.

Article Abstract

There is an urgent need for novel therapeutic approaches to treat Alzheimer's disease (AD) with the ability to both alleviate the clinical symptoms and halt the progression of the disease. AD is characterized by the accumulation of amyloid-β (Aβ) peptides which are generated through the sequential proteolytic cleavage of the amyloid precursor protein (APP). Previous studies reported that Mint2, a neuronal adaptor protein binding both APP and the γ-secretase complex, affects APP processing and formation of pathogenic Aβ. However, there have been contradicting results concerning whether Mint2 has a facilitative or suppressive effect on Aβ generation. Herein, we deciphered the APP-Mint2 protein-protein interaction (PPI) via extensive probing of both backbone H-bond and side-chain interactions. We also developed a proteolytically stable, high-affinity peptide targeting the APP-Mint2 interaction. We found that both an APP binding-deficient Mint2 variant and a cell-permeable PPI inhibitor significantly reduced Aβ levels in a neuronal model of AD. Together, these findings demonstrate a facilitative role of Mint2 in Aβ formation, and the combination of genetic and pharmacological approaches suggests that targeting Mint2 is a promising therapeutic strategy to reduce pathogenic Aβ levels.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176898PMC
http://dx.doi.org/10.1021/jacs.0c10696DOI Listing

Publication Analysis

Top Keywords

targeting app-mint2
8
app-mint2 protein-protein
8
protein-protein interaction
8
pathogenic aβ
8
aβ levels
8
aβ
6
mint2
5
interaction peptide-based
4
peptide-based inhibitor
4
inhibitor reduces
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!