<p style="text-align: justify; font-size: 16px; line-height: 20px;">The important role of microglia in Alzheimer’s disease (AD) is well recognized, however their molecular and functional diversity and underlying mechanisms still remain controversial. To transcriptionally and functionally characterize the diversity of microglia in AD and aging, we isolated the amyloid plaque-containing (XO4+) and non-containing (XO4-) microglia from an AD mouse model.</p> <p style="text-align: justify; font-size: 16px; line-height: 20px;">Transcriptomics analysis unveiled independent transcriptional trajectories in ageing and AD. XO4+ microglial transcriptomes linked plaque phagocytosis to dysregulated expression of bona fide late onset AD genetic risk factors. To determine whether the XO4+ signature occurs in human AD, we applied single-nucleus RNA sequencing to entorhinal cortex samples from control and AD brains (n = 6 per group).</p> <p style="text-align: justify; font-size: 16px; line-height: 20px;">We revealed that features of the XO4+ transcriptional program are present in a subset of human microglia from AD patients. Conversely, XO4- microglia in AD displayed an accelerated ageing signature and contained more intracellular post synaptic material than plaque-containing microglia, despite reduced active synaptosome phagocytosis. We identified Hif1α as a regulator of the XO4-/XO4+ axis, and validated the functional role of Hif1α on synaptosome phagocytosis in vitro. Together these findings unveiled the molecular mechanism underpinning the functional diversity of microglia in AD.</p> <p style="text-align: justify; font-size: 16px; line-height: 20px;">Finally, our single nuclei resource describes cell-type-specific gene expression patterns in AD, and allowed us to discover how genetic predisposition to AD manifests in specific brain cell subpopulations and to predict the master switches involved. These results provide insights into the coordinated control of AD risk genes and their cell-type-specific contribution to disease susceptibility.</p>
- Webinar Speakers
Alexandra Grubman
Department of Anatomy and Developmental Biology and Australian Regenerative Medicine Institute,
Monash UniversityAlex’s PhD research as an NHMRC Dora Lush Scholar at Monash University discovered that host responses to Helicobacter pylori involve direct killing of these bacteria by antimicrobial peptides, activated via delivery of bacterial cell wall components to the intracellular pathogen recognition receptor, Nod1. After her PhD, Alex joined the laboratory of A/Prof Anthony White at the University of Melbourne, showing impaired subcellular biometal homeostasis and neuroinflammation in the childhood neurodegenerative disorders, Batten Diseases. Alex received the Melbourne Neuroscience Institute Fellowship in 2015, and in 2016, Alex joined Prof Jose Polo’s lab at Monash University as an NHMRC-ARC Dementia Research Development Fellow to focus on the molecular mechanisms that govern cell identity and the functional diversity of microglia in Alzheimer’s Disease. Together with collaborators from Monash and Duke-NUS in Singapore, using single cell transcriptomics, Alex’s research uncovered the changes occurring in the brain of AD patients (Grubman, Chew Ouyang et al 2019 Nat. Neurosci.) and in microglia in a mouse model of Alzheimer’s disease (Grubman, Choo, Chew et al 2019 BioRxiv). Furthermore, the team created an interactive brain cell atlas, providing a useful online resource to dissect mechanisms of cell heterogeneity and dysfunction in Alzheimer’s disease.
- Webinar Abstract
John F. Ouyang
Research Fellow, (Duke-NUS) Medical School,
Duke-National University of SingaporeJohn F. Ouyang is a research fellow based in Duke-National University of Singapore (Duke-NUS) Medical School, Singapore. He has a PhD in computational chemistry and transitioned into bioinformatics in his research fellow stint. He is interested in the understanding the master regulators and signalling cues driving cell fate transitions during somatic cell reprogramming and disease progression. Despite being a budding bioinformatician, John has several publications in top international journals such as Nature, Nature Neuroscience and Genome Biology.