Vignesh Subramanian ’24

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory, critical thinking skills, and behavioral capabilities that typically worsens with age. As the most common form of late-stage dementia, numerous risk alleles – variants of a gene that make a particular disease’s development more likely – have been identified for AD. Prominent among these is the triggering receptor expressed on myeloid cells 2 (TREM2), a transmembrane protein ordinarily responsible for recruiting kinases (catalytic enzymes that energize reactions via phosphate transfer) to trigger signaling cascades. These cascades in turn regulate the functions of microglia, the specialized immune cells of the central nervous system that engulf and eliminate damaged neurons and pathogens. However, in the disease state, the presence of a variant of the TREM2 gene known as R47H has been associated with an increased risk of late-onset AD for unknown reasons. A study led by Dr. Gan of Weill Cornell Medicine sought to better characterize the relationship between this mutation and AD progression.

Researchers identified 46 patients with AD carrying either the common variant (CV) or R47H variant of TREM2 via single-nucleus RNA sequencing (snRNA-seq). Researchers then used a CRISPR-based genetic tool to replace one allele of mouse Trem2 (mTrem2) with CV- or R47H- human Trem2 (hTREM2), generating a mouse model with spatial memory deficits that could be used to comparatively examine functional changes induced by the latter variant. Finally, the models were treated with MK-2206 (a cancer drug currently in clinical trials), which pharmacologically inhibited signaling by AKT, a family of kinases that mediates cell proliferation and apoptosis.

The subsequent snRNA-seq analysis of the human patients’ mid-frontal cortical tissues revealed that the R47H mutation had induced transcriptional changes in all assessed cell types (microglia and otherwise), while human R47H AD microglia subclusters demonstrated hyperactivation of inflammatory and AKT signaling via common immune pathways. More specifically, researchers found that R47H-hTREM2 presence exacerbates inflammation, spatial memory deficits, and both microglial signatures and AKT signaling. Conversely, researchers also found that inhibition of AKT signaling in drug-treated mice contained the spread of synaptic toxicity, virtually eliminating the proinflammatory microglial subpopulation among R47H variant mice. Taken together, these findings conclude that R47H-TREM2 generates heightened proinflammatory disease states, that suppression of maladaptive innate immune responses like hyperactive AKT signaling can slow the progression of microglial tauopathy and that drugs that correct a substantial number of R47H-altered genes may accomplish just that. Future studies may correlate the observations made of human subjects with improvements in the mouse models’ prognoses, potentially revealing a new target for microglia-based AD therapies.

Works Cited:

[1] F. Sayed, et al., AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation. Science Translational Medicine 13, 1-16 (2021). doi: 10.1126/scitranslmed.abe3947

[2] Image retrieved from: https://commons.wikimedia.org/wiki/File:Microglia_and_neurons.jpg