Cyclin-dependent kinase 5 (cdk5) has been implicated in Alzheimer's disease (AD) pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription (STAT1/3) was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2329816 | PMC |
| http://dx.doi.org/10.1016/j.neuron.2008.02.024 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
From Molecular to Radionuclide and Pharmacological Aspects in Transthyretin Cardiac Amyloidosis.
Int J Mol Sci
December 2024
Clinic of Nuclear Medicine Central University Emergency Military Hospital "Dr Carol Davila", 10825 Bucharest, Romania.
Amyloidosis is a rare pathology characterized by protein deposits in various organs and tissues. Cardiac amyloidosis (CA) can be caused by various protein deposits, but transthyretin amyloidosis (ATTR) and immunoglobulin light chain (AL) are the most frequent pathologies. Protein misfolding can be induced by several factors such as oxidative stress, genetic mutations, aging, chronic inflammation, and neoplastic disorders.
View Article and Find Full Text PDFLocalized light chain amyloidosis of the stomach that regressed after eradication of Helicobacter pylori over 15 years of follow-up: a case report and new hypothesis.
Clin J Gastroenterol
January 2025
Department of Gastroenterology, Saiseikai Kanazawa Hospital, Ni-13-6 Akatsuchimachi, Kanazawa, Ishikawa, 920-0353, Japan.
Localized light chain amyloidosis is considered to be a plasmacytic B-cell lymphoproliferative disorder caused by antigenic induction. A hypothesis has been proposed that antigen-induced local plasmacytic B cells produce amyloidogenic proteins that are processed into amyloid fibrils in giant cells leading to amyloid fibril deposition. However, the inciting antigen exposure or immune response that signals plasmacytic B-cell infiltration, activation, and selection, is unknown.
View Article and Find Full Text PDFEfficient Biochemical Method for Characterizing and Classifying Related Amyloidogenic Peptides.
Anal Chem
January 2025
Institut de Recherche en Santé, Environnement et Travail (Irset)─Inserm─EHESP, UMR_S 1085, Université de Rennes, 9 av. du Professeur Léon Bernard, F-35042 Rennes, France.
Amyloidosis is a group of proteinopathies characterized by the systemic or organ-specific deposition of proteins in the form of amyloid fibers. Nearly 40 proteins play a role in these pathologies, and the structures of the associated fibers are beginning to be determined by Cryo-EM. However, the molecular events underlying the process, such as fiber nucleation and elongation, are poorly understood, which impairs developing efficient therapies.
View Article and Find Full Text PDFAlterations 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 PDFAPP lysine 612 lactylation ameliorates amyloid pathology and memory decline in Alzheimer's disease.
J Clin Invest
January 2025
Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Article Synopsis
- Posttranslational modification (PTM) of the amyloid precursor protein (APP), particularly lactylation, is linked to the development of Alzheimer's disease (AD), but its specific role is still unclear.
- Research showed reduced APP lactylation in AD patients and models, identifying lysine 612 as a key lactylation site, which affects APP processing and Aβ generation.
- A lactyl-mimicking mutant enhanced APP trafficking and reduced cognitive decline by modifying APP interactions, suggesting that targeting APP lactylation may offer new therapeutic avenues for Alzheimer's disease.
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!