Alzheimer´s disease (AD) is a neurodegenerative disease and most common form of dementia. It is characterized by neuronal loss, extracellular amyloid b (Ab) plaques and intraneuronal deposits of neurofibrillary tangles (NFTs)(Selkoe, 2003). AD pathology also manifests reactive gliosis that reflects the activation of microglia and astrocytes. Besides above, myelin degeneration has been increasingly proposed as a key contributor to AD. Microglia are resident immune cells in the central nervous system (CNS). They play essential roles during development by modulating brain homeostasis, neuronal circuits and synaptic pruning(Schafer et al., 2012). In brain diseases, microglia are responsible for inflammatory responses, including phagocytosis and the secretion of soluble factors, such as cytokines, that contribute to immune responses and tissue repair. In the context of AD, activated microglia can reduce Ab aggregation by increasing its phagocytosis, clearance and degradation(Frautschy et al., 1998). Microglia have a long lifespan(Réu et al., 2017), which gives them the capacity to retain their inflammatory past, potentially leading to long-lasting effects. Although inflammation in the body is intended to be protective, an aggressive inflammatory reaction can lead to or contribute to pathological conditions(Heneka et al., 2001). Increasing evidence and my recent study(Yang et al., 2023) have shown that microglia primed with systemic infections had contradictory responses in AD animal models (Tejera et al., 2019; Wendeln et al., 2018). These studies manifest diverse microglia profiles and their impact on Ab accumulation depends on the stimulation and the duration of exposure. Moreover, other cell types, such as astrocytes and oligodendrocytes, may also play roles in AD progression.
The research project aims to identify distinct phenotypes of neurons and one glial cell type (microglia, astrocytes, and oligodendrocytes) through single-cell RNA sequencing method. The objective is to investigate how early-life inflammation influences their transcriptomic and proteomic alterations, with the ultimate goal of targeting specific pathways that modulate neuron-glia interactions. Additionally, preclinical findings will be validated using data from Alzheimer’s disease (AD) patient cohorts at the project’s conclusion.
Supervisor and contact: Yiyi Yang, yiyi.yang@med.lu.se
Affiliation: Experimental neuroinflammation laboratory, Department of Experimental Medical Sciences (EMV), Faculty of Medicine.