A Microglia-Containing 3D Human Brain Organoid for Studying HSV-1-Induced Alzheimer’s Disease

Abstract

The pathogenesis of Alzheimer’s disease (AD) has been widely associated with amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). Recent research suggests that herpes simplex virus type 1 (HSV-1) may play a role in the development of AD by triggering neuroinflammation. Microglia, as the immune cells of the central nervous system, contribute significantly to AD-related neuroinflammatory processes, but their precise role in HSV-1-induced AD is not fully understood. This study aimed to explore the relationship between HSV-1 infection and AD pathology using microglia-containing human brain organoids (MC-HBOs). We found that after infecting MC-HBOs with HSV-1, there was a significant increase in Aβ deposition, NFTs, and neuron loss. Microglia appeared to facilitate amyloid plaque formation and neurofibrillary tangle development, as well as participate in the clearance of Aβ. The activation of microglia also correlated with elevated levels of pro-inflammatory cytokines such as IL-6, enhancing neuroinflammation. Furthermore, inhibiting IL-6 expression in microglia reduced Aβ aggregation, suggesting that microglia may be a therapeutic target for preventing or slowing the progression of AD. This model highlights the important role of microglia in HSV-1-induced AD and offers potential strategies for future therapeutic interventions.