Ciliary p75 neurotrophin receptor (p75NTR) facilitates the enrichment of exogenous amyloid beta (Aβ 1-42) peptide and promotes oxidative stress in human hippocampal astrocytes.

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.