Mutations in the amyloid precursor protein (APP) cause early-onset Alzheimer's disease (AD), but the only genetic risk factor for late-onset AD is the varepsilon4 allele of apolipoprotein E (apoE), a major cholesterol carrier. Using Cre-lox conditional knockout mice, we demonstrate that lipoprotein receptor LRP1 expression regulates apoE and cholesterol levels within the CNS. We also found that deletion of APP and its homolog APLP2, or components of the gamma-secretase complex, significantly enhanced the expression and function of LRP1, which was reversed by forced expression of the APP intracellular domain (AICD). We further show that AICD, together with Fe65 and Tip60, interacts with the LRP1 promoter and suppresses its transcription. Together, our findings support that the gamma-secretase cleavage of APP plays a central role in regulating apoE and cholesterol metabolism in the CNS via LRP1 and establish a biological linkage between APP and apoE, the two major genetic determinants of AD.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2045076 | PMC |
| http://dx.doi.org/10.1016/j.neuron.2007.08.008 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Association between gene polymorphisms and glaucoma susceptibility among Africans: a systematic review and meta-analysis.
Ophthalmic Genet
January 2025
School of Optometry, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
Purpose: This study sought to analyze the effect of allele mutations and gene functions specific to glaucoma susceptibility among Africans.
Methods: Potentially relevant studies were retrieved from major bibliographic databases (PubMed, Scopus, and Web of Science). Data were extracted and study-specific estimates were meta-analyzed using various models to obtain pooled results.
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 PDFImmunohistochemical labeling of ongoing axonal degeneration 10 days following cervical contusion spinal cord injury in the rat.
Spinal Cord
January 2025
McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
Study Design: Experimental Animal Study.
Objective: To continue validating an antibody which targets an epitope of neurofilament light chain (NF-L) only available during neurodegeneration and to utilize the antibody to describe the pattern of axonal degeneration 10 days post-unilateral C4 contusion in the rat.
Setting: University of Florida laboratory in Gainesville, USA.
The Role of Oligodendrocyte Lineage Cells in the Pathogenesis of Alzheimer's Disease.
Neurochem Res
January 2025
Department of Neurology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Alzheimer's disease (AD) is a central nervous system degenerative disease with a stealthy onset and a progressive course characterized by memory loss, cognitive dysfunction, and abnormal psychological and behavioral symptoms. However, the pathogenesis of AD remains elusive. An increasing number of studies have shown that oligodendrocyte progenitor cells (OPCs) and oligodendroglial lineage cells (OLGs), especially OPCs and mature oligodendrocytes (OLGs), which are derived from OPCs, play important roles in the pathogenesis of AD.
View Article and Find Full Text PDFIntroduction: Previous studies have examined the predictive accuracy of plasma amyloid beta (Aβ) biomarkers in clinical cohorts. However, their accuracy for predicting amyloid-positive patients in community-based cohorts is unclear. This study aimed to determine the predictive accuracy of Aβ precursor protein 669-711/Aβ1-42, Aβ1-40/1-42 and their composite biomarkers for brain amyloid deposition or the clinical progression in community-dwelling older adults with mild cognitive impairment (MCI).
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!