Human astrocytes from healthy individuals and Alzheimer’s patients respond differently to Aβ1–42 oligomers, triggering distinct paths of reactivity and senescence

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by cognitive decline, amyloid-β (Aβ) plaques, and neurofibrillary tangles. Aβ_1–42 oligomers exert neurotoxic and pro-inflammatory effects. Astrocytes maintain brain homeostasis, and their dysfunction contributes to AD progression. This study investigates the impact of Aβ_1–42 oligomers on primary human astrocytes from healthy individuals and AD patients. Our findings show that astrocytes from both groups internalise Aβ_1–42 oligomers. In healthy astrocytes, internalisation enhances proteasome activity, whereas in AD astrocytes, it reduces it. Aβ_1–42 oligomers induce calcium dyshomeostasis and mitochondrial membrane potential alterations in both groups. Interestingly, oligomers induce apoptosis in a subset of healthy astrocytes, while surviving ones become reactive and hyperproliferative, releasing neuroinflammatory and neurotrophic molecules. Conversely, Aβ_1–42 drives AD astrocytes into senescence, characterised by increased β-galactosidase activity, p14^ARF expression, senescence-associated secretory phenotype (SASP), and heterochromatin foci. Importantly, conditioned media from Aβ_1–42-treated AD astrocytes, but not from healthy ones, cause death of differentiated SH-SY5Y neuron-like cells, suggesting that senescent astrocytes contribute to neurotoxicity. These findings reveal differential astrocytic responses to Aβ_1–42 oligomers, emphasising the importance of astrocyte senescence in AD pathogenesis. This research offers insight into cellular mechanisms underlying AD and may support the development of innovative therapeutic strategies for neurodegenerative diseases.