In the realm of Alzheimer’s research, it is widely acknowledged that microglia research is still in its early stages, leaving much to be discovered. Recently, microglia have emerged as pivotal players in the development of late-onset Alzheimer’s. However, their exact role within the disease mechanism is still a mystery. The groundbreaking research conducted by Li, Shen, and their team, is truly a breakthrough in how we view the function of microglia in Alzheimer’s.
Here is What we Knew:
Microglia cells, deriving from the Classical Greek terms, “micro” (small) and “glia” (glue) – are the resident immune cells of the brain. Their primary role is to surveil the microenvironment within the brain and respond to pathogens and damage. Microglia can also mediate synapse loss (a downstream effect of amyloidosis, tauopathy, inflammation, and other mechanisms occurring in Alzheimer’s. In Layman’s terms, it is most closely correlated with cognitive decline). However, they can also do the complete opposite. Microglia can worsen tau pathology (an abnormal accumulation of tau proteins in the central nervous system) and release inflammatory substances that harm neurons directly or activate neurotoxic astrocytes. There are still a lot of questions relating to the dual nature of microglia in either aiding or harming the same mechanisms. Many, however, attribute this phenomenon to aging or genetic susceptibility. As toxic amyloid species accumulate, tau pathology escalates within stressed or damaged neurons. This, in turn, prompts microglia to transform into a nonconstructive and inflammatory state. In this state, they eat synapses, secrete neurotoxic cytokines that damage neurons, and facilitate propagation in the spread of tau pathology. Microglia appears to be a double-edged sword for Alzheimer’s disease, complicating how we approach therapies specifically targeting microglia.
This is where Li and her colleagues come in:
They began their research with 37 genetic markers associated with Alzheimer’s, concentrating on risk variants and their functional regions known as candidate cis-regulatory regions (cCRE). They employed a meticulous process called fine-mapping, scrutinizing each locus while taking into account epigenetic marks and 3D genome integration to gauge their significance in microglial function. Once they pinpointed variants likely to impact Alzheimer’s through gene regulation in microglia, they conducted CRISPR Interference (CRISPRi) screening experiments to precisely identify the regions influencing gene expression. Remarkably, they discovered that deactivating one region could affect an entire group of genes, suggesting that each region might harbor multiple genetic variants linked to Alzheimer’s. To accurately pinpoint the specific variant associated with Alzheimer’s, the team utilized a precise editing technique called prime editing, enabling them to introduce single DNA base substitutions and assess individual variant functions. Through this method, they successfully identified a specific variant responsible for the expression of TSPAN14, a protein-coding gene.
They then examined how this particular variant influences various cellular mechanisms, including the maturation of a protein called ADAM10 and the breakdown of another protein called soluble TREM2 in microglia. Notably, all three of these genes are already recognized as being associated with Alzheimer’s disease. This study illuminates the connection between this specific microglial variant and various cellular mechanisms, extending beyond the regulation of gene expression.
A Shift in Alzheimer’s Research
The study yielded significant results, uncovering 181 previously unidentified regions of interest that encompassed 308 prioritized variants. These variants, previously overlooked in their association with Alzheimer’s disease, were found to have functional implications in microglia that extend beyond the regulation of gene expression. This discovery provides a novel foundation for future research, offering a platform from which other scientists can identify further causal variants of Alzheimer’s, make accurate disease risk predictions, and formulate more effective therapeutic interventions.
Studies like this not only aid in identifying distinct microglia subsets but also uncover key molecules and variants crucial for Alzheimer’s disease progression, paving the way for innovative therapeutic approaches. These studies also serve as a valuable resource for the development of biomarkers to track disease advancement. As most microglia subsets are characterized through transcriptional profiling, it is imperative to understand their functional roles as a foundation for therapeutic strategies. Comprehending the dynamic shifts in microglia subsets throughout disease progression is vital for effective monitoring and treatment.