Year: 2026
Type: article
Abstract: Astrocytes are essential for neuronal health, and astrocyte reactivity is a hallmark of neuroinflammation, a key regulator of Alzheimer’s disease (AD) pathology. Despite increasing evidence linking neuroinflammation and astrocyte reactivity to AD, the precise role of astrocytes in disease progression remains unclear. In this study, we used a three-dimensional (3D) human cell culture model of AD (3D-AD cultures), which exhibits amyloid-β (Aβ)-driven tau pathology, alongside 3D-control cultures to investigate the involvement of astrocytes in Aβ accumulation and tau phosphorylation. Astrocyte ablation using L-alpha-aminoadipate, an astrocyte-selective gliotoxin, increased Aβ40 levels and tau phosphorylation at Thr231 without significantly affecting Aβ42 levels, resulting in a reduced Aβ42/Aβ40 ratio in 3D-AD cultures, suggesting that astrocytes may exert protective effects against tau pathology. Conversely, inducing astrocyte reactivity with a combination of neuroinflammatory factors (TNF-α, IL-1α, and C1q; TIC) elevated Aβ40 and Aβ42 levels but did not significantly affect tau phosphorylation at Thr231, highlighting a role for neuroinflammatory astrocyte reactivity in Aβ pathology. We also observed rapid ERK activation and increased pro-inflammatory cytokine release during TIC-induced astrocyte reactivity, followed by complement C3 upregulation. Pharmacological ERK inhibition attenuated the TIC-induced increase in lactate dehydrogenase (LDH) release but did not prevent the increase in Aβ levels, suggesting that ERK signaling contributes to TIC-induced cytotoxicity without directly mediating the associated Aβ accumulation. Collectively, these findings suggest that astrocytes act as key modulators of AD pathology by protecting against Aβ and tau accumulation under baseline conditions while promoting Aβ buildup and neuroinflammatory toxicity when they become reactive.
Source: Frontiers in Aging
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,077
OpenAlex ID: W7225761711