The amyloidogenic processing pathway of the APP (amyloid precursor protein) generates Abeta (amyloid beta-peptide), the major constituent in Alzheimer's disease senile plaques. This processing is catalysed by two unusual membrane-localized aspartic proteinases, beta-secretase [BACE1 (beta-site APP-cleaving enzyme 1)] and the gamma-secretase complex. There is a clear link between APP processing and copper homoeostasis in the brain. APP binds copper and zinc in the extracellular domain and Abeta also binds copper, zinc and iron. We have found that a 24-residue peptide corresponding to the C-terminal domain of BACE1 binds a single copper(I) atom with high affinity through cysteine residues. We also observed that the cytoplasmic domain of BACE1 interacts with CCS, the dedicated copper chaperone for SOD1 (superoxide dismutase 1). Overproduction of BACE1 reduces SOD1 activity in cells. Consequently, SOD1 activity, cytosolic copper and ectodomain cleavage of APP are linked through BACE1.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1042/BST0350571 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Alterations in the Processing of Platelet APP (Amyloid Beta Precursor Protein) in Alzheimer Disease: The Possible Nexus.
Neuropsychopharmacol Rep
March 2025
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
Alzheimer's disease (AD) is the most common neurodegenerative disease associated with the development of dementia. The hallmarks of AD neuropathology are accumulations of amyloid peptide (Aβ) and neurofibrillary tangles (NFTs). Aβ is derived from the processing of APP (amyloid beta precursor protein) by BACE1 (beta-secretase 1) and γ-secretase through an amyloidogenic pathway.
View Article and Find Full Text PDFInhibition of zDHHC7-driven protein S-palmitoylation prevents cognitive deficits in an experimental model of Alzheimer's disease.
Proc Natl Acad Sci U S A
December 2024
Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome 00168, Italy.
Protein post-translational modifications (PTM) play a crucial role in the modulation of synaptic function and their alterations are involved in the onset and progression of neurodegenerative disorders. S-palmitoylation is a PTM catalyzed by zinc finger DHHC domain containing (zDHHC) S-acyltransferases that affects both localization and activity of proteins regulating synaptic plasticity and amyloid-β (Aβ) metabolism. Here, we found significant increases of both zDHHC7 expression and protein S-palmitoylation in hippocampi of both 3×Tg-AD mice and post-mortem Alzheimer's disease (AD) patients.
View Article and Find Full Text PDFResearch progress on the association of insulin resistance with type 2 diabetes mellitus and Alzheimer's disease.
Metab Brain Dis
November 2024
Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, 310013, Zhejiang, P.R. China.
Type 2 diabetes mellitus (T2DM) is a metabolic disorder that is characterized by insulin resistance and hyperglycemia. It is also known to be a risk factor for Alzheimer's disease (AD). Insulin plays a crucial role in regulating the body's metabolism and is responsible for activating the Phosphoinotide-3-Kinase (PI3K)/Protein Kinase B (Akt) signaling pathway.
View Article and Find Full Text PDFMolecular mechanism underlying effect of D93 and D289 protonation states on inhibitor-BACE1 binding: exploration from multiple independent Gaussian accelerated molecular dynamics and deep learning.
SAR QSAR Environ Res
October 2024
Center for Medical Artificial Intelligence, Shandong University of Traditional Chinese Medicine, Qingdao, China.
BACE1 has been regarded as an essential drug design target for treating Alzheimer's disease (AD). Multiple independent Gaussian accelerated molecular dynamics simulations (GaMD), deep learning (DL), and molecular mechanics general Born surface area (MM-GBSA) method are integrated to elucidate the molecular mechanism underlying the effect of D93 and D289 protonation on binding of inhibitors OV6 and 4B2 to BACE1. The GaMD trajectory-based DL successfully identifies significant function domains.
View Article and Find Full Text PDFAn Insight into Medicinal Chemistry and SAR Studies of Cholinesterase and BACE-1 Inhibitors for Alzheimer's Disease.
CNS Neurol Disord Drug Targets
October 2024
University Institute of Pharmaceutical Sciences and Research, Baba Farid University of Health Sciences, Faridkot, Punjab, India.
Alzheimer's Disease (AD) is a serious neurodegenerative condition that predominantly impacts the cholinergic neurons of the entorhinal cortex and hippocampal regions, playing a critical role in learning, navigation, and brain processing. This paper aims to discuss the three main hypotheses of Alzheimer's disease, focusing on neurotoxicity and neurodegeneration caused by mitochondrial dysfunction and ROS production, particularly analyzing the susceptibility differences between genders. Our comprehensive review focuses on significant findings from the past five years, particularly on Cholinesterase (ChE) and BACE-1 inhibitors.
View Article and Find Full Text PDFWant 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!