Molecular players in neuroinflammation and Alzheimer’s disease
Alzheimer’s disease (AD) is a neurodegenerative condition that has been tightly linked with chronic neuroinflammation. The accumulation of abnormal amyloid beta and tau protein aggregates in neuronal cells in the brain triggers immune responses and activates microglia, the primary immune cells of the central nervous system. Failure to clear protein aggregates and chronic microglia activation perpetuates neuroinflammation, damaging neurons and impairing synaptic function. Microglia are emerging as key players in several neurodevelopmental and neurodegenerative diseases because of their role in immune surveillance, in detecting and responding to local brain injury as well as abnormal neuronal activity. Moreover, genetic studies have identified several AD-risk genes to be highly expressed in microglia.
Microglia generated from induced pluripotent stem cells
Undertaken with the support of the Marie Skłodowska-Curie Actions programme, the iMIND project used induced pluripotent stem cells (iPSCs) to generate microglia cells in vitro and study the normal and pathological functions of disease-associated genes. “Gaining insight into the normal function of disease-associated genes will enhance our understanding of the underlying mechanisms of AD,” explains the MSCA research fellow Alberto Granzotto. The project focused on the TREM2 cell surface receptor which is predominantly expressed in microglia, and binds a variety of ligands including amyloid beta peptides. Ligand binding triggers downstream intracellular events implicated in various microglia functions such as proliferation, phagocytosis and survival.
Insight into the role of TREM2 in microglia and AD
Although rare, TREM2 loss-of-function variants have been linked with an increased risk of AD, the underlying molecular mechanisms connecting deficits in TREM2 signalling with AD phenotype are not well understood. Granzotto and colleagues set out to elucidate how calcium – a ubiquitous second messenger involved in numerous cellular processes – is affected in microglia lacking TREM2. Neuroinflammation has been associated with altered calcium signalling and microglia, in particular, showing altered calcium responses in AD mouse models. In engineered TREM2 knockout microglia, researchers detected aberrant calcium signalling upon sensing of environmental cues linked to tissue damage. This indicated that TREM2 is implicated in the regulation of the calcium signalling pathway and seems to influence cytosolic calcium levels. Microglial motility and chemotaxis were primarily affected as a result of perturbed calcium signalling. This clearly underscores the importance of calcium signalling for optimal microglia migration capacity and points towards novel pathways that might be involved in AD.
New therapeutic approaches ahead for AD
The iMIND research provided essential evidence regarding TREM2 signalling. Results hold significant relevance in the context of clinical trials evaluating the efficacy of TREM2-activating antibodies as a potential therapeutic approach for AD. “Our findings identify novel, potentially druggable targets aimed at counteracting neuroinflammatory processes linked to AD pathogenesis,” emphasises Granzotto. Future plans include the investigation of the mechanisms that link calcium signalling to motility and migration in microglia. Defective microglial motility towards damaged areas of the central nervous system appears to be a key feature of neurodegeneration. Therefore, insights into microglial migration mechanisms are expected to aid in the understanding and resolution of neuroinflammatory diseases.
Keywords
iMIND, Alzheimer’s disease, AD, microglia, induced pluripotent stem cells, TREM2, motility, chemotaxis
