Ciliary p75 neurotrophin receptor (p75NTR) facilitates the enrichment of exogenous amyloid beta (Aβ 1-42) peptide and promotes oxidative stress in human hippocampal astrocytes. BMC Mol Cell Biol 2026 Mar 18;27(1)
Date
03/19/2026Pubmed ID
41851829Pubmed Central ID
PMC13122876DOI
10.1186/s12860-026-00581-zScopus ID
2-s2.0-105037047856 (requires institutional sign-in at Scopus site)Abstract
Accumulation of amyloid beta 1–42 (Aβ42) peptide in the extracellular space in the brain is a major observation in Alzheimer’s Disease (AD)-related pathology. Astrocytes are known to play pivotal role in clearing the extracellular aβ peptide from the brain, and the underlying mechanism of Aβ42 peptide clearance remains underappreciated. Like other cell types in the brain, astrocytes have primary cilia, a nonmotile microtubule-based organelle. Aβ42 peptide is reported to affect cilia length or structure in multiple cell types including neurons and inhibit ciliary p75 neurotrophin receptor (p75NTR). To date, the relationship between the extracellular Aβ42 and the astrocytic cilia has not been established. In this work, using primary human hippocampal astrocytes and post-mortem brain specimens obtained from AD patients, we performed molecular, flow cytometry and imaging approaches to investigate the relationship of astrocytic cilia and extracellular Aβ42 peptide. Our data demonstrate that the exogenous Aβ42 peptide treatment in vitro, induces expression of p75NTR in astrocyte cilia in a dose-dependent fashion. We also observed the enrichment of exogenous Aβ42 peptide in the astrocyte cilia and the plasma membrane of astrocytes. In exogenous Aβ42 peptide-treated groups, we observed aberrant proliferation and cell cycle, increased oxidative stress and apoptosis. Interestingly, we observed an enrichment of astrocytic p75NTR expression in the human post-mortem AD-brain. Silencing RNA (siRNA)-mediated knockdown of p75NTR gene significantly minimized the enrichment of exogenous Aβ peptide and the oxidative stress in primary hippocampal astrocytes in vitro. These studies unravel a molecular signaling mechanism that involves Aβ42 peptide-induced p75NTR-mediated oxidative stress that affects overall astrocyte health in AD-associated pathology.
Author List
Gupta A, Thirugnanam K, Bice Z, Lowman AK, Rarick KR, LaViolette PS, Pan A, Franczak M, Ramchandran RAuthors
Peter LaViolette PhD Vice Chair, Professor in the Radiology department at Medical College of WisconsinRamani Ramchandran PhD Professor in the Pediatrics department at Medical College of Wisconsin
Karthikeyan Thirugnanam Research Scientist I in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Alzheimer DiseaseAmyloid beta-Peptides
Apoptosis
Astrocytes
Cells, Cultured
Cilia
Hippocampus
Humans
Nerve Tissue Proteins
Oxidative Stress
Peptide Fragments
Receptors, Nerve Growth Factor
