Journal Article

Human microglia differentially respond to β‐amyloid, tau, and combined Alzheimer's disease pathologies in vivo

Shabestari, Sepideh Kiani, Silva, Jorge, Spitale, Robert C., Tu, Christina, McQuade, Amanda, Chadarevian, Jean Paul, Mgerian, Michael Armen, Blurton‐Jones, Mathew, Davtyan, Hayk, Mansour, Kimiya, Hasselmann, Jonathan, Eskandari‐Sedighi, Ghazaleh, Keulen, Zahara, England, Whitney, Beck, Jaclyn, Coburn, Morgan A.

2025

Overview

INTRODUCTION Recent studies have identified important species‐dependent differences in the response of microglia to β‐amyloid (Aβ) pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occur in Alzheimer's disease (AD) remains unclear. METHODS We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell‐derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling. RESULTS The combined amyloid and tau pathologies induced robust type‐I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct “rod” morphology in human microglia. The rod morphology could be induced with type‐I interferon treatment in vitro. DISCUSSION We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo. Highlights Amyloid pathology promotes the rapid development of neurofibrillary tangles and neuronal loss in a novel chimeric model of AD. Combined Alzheimer's disease pathologies lead to an expansion of disease‐associated microglia (DAM) and exacerbate Interferon‐responsive and cytokine/chemokine‐enriched states in xenotransplanted human microglia. The combination of amyloid and tau promotes the development of a distinctive rod microglial phenotype that closely correlates with tau pathology and neurodegeneration. Rod morphology and transcriptional changes can be modeled in vitro by treatment of induced pluripotent stem cells (iPSC) ‐microglia with type‐I interferons.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / amyloid beta / Amyloid beta-Peptides - metabolism / Animals / Dams / Disease / Disease Models, Animal / human microglia / Humans / Induced / Interferon / iPSC / Mice / Mice, Transgenic / Microglia - metabolism / Microglia - pathology / Morphology / Neurofibrillary Tangles - metabolism / Neurofibrillary Tangles - pathology / Pathology / Plaque, Amyloid - metabolism / Plaque, Amyloid - pathology / Postpartum period / rod microglia / Stem cells / tau / tau Proteins - metabolism / Transplants & implants / type I interferon / Xenografts