Background

In the progression of Alzheimer's disease (AD), myeloid cells in the brain, including microglia and perivascular macrophages (PVM), play a crucial role in clearing brain waste and controlling immune responses. While immunological approaches for AD inhibition have been explored, the dynamic changes and activation states of these cells have not been precisely understood. Previous mouse studies have not fully reflected the complex diversity and long-term pathology of human brain immune cells. Post-mortem brain analysis has also been limited by sample size, making it difficult to capture rare subtypes that undergo subtle changes. Therefore, a large-scale transcriptomic mapping is needed to track the stage-by-stage changes associated with aging and disease.

Key Findings

The research team at the Icahn School of Medicine at Mount Sinai analyzed 830,005 myeloid cells derived from the prefrontal cortex (PFC) of 1,607 donors. The myeloid cells were divided into six classes and 13 transcriptional subtypes. As the disease progresses, the number of FERM domain-containing protein 4A (FRMD4A)-positive cells, which maintain homeostasis, decreased, while the number of phosphatidylinositol binding clathrin assembly protein (PICALM)-positive subtypes increased.

This led to the identification of a subtype in which the expression of glycoprotein nonmetastatic melanoma protein B (GPNMB) increased sharply during disease exacerbation. This GPNMB subtype was strongly expressed in the group with a high polygenic risk score (PRS) and exhibited excellent amyloid-beta (Aβ) clearance ability.

Regulatory network analysis revealed that microphthalmia-associated transcription factor (MITF) is the main regulator that governs the phagocytic function of this GPNMB subtype. In human microglia cell line HMC3, activation of MITF promoted phagocytic activity, while inhibition of MITF blocked clearance activity. This protective effect was determined by the presence or absence of triggering receptor expressed on myeloid cells 2 (TREM2). When TREM2 was removed from human stem cell-derived microglia, the expression of GPNMB and MITF was completely stopped. In the brain tissue of 42 patients with heterozygous TREM2 mutations, the expression of the GPNMB subtype was lower than in 39 wild-type patients, and Mitf activity was also suppressed in Trem2-deficient mice (n=3). This interaction is mediated by the apolipoprotein E (APOE)-sortilin-related receptor 1 (SORL1) and APOE-TREM2 pathways.

Significance and Prospects

This study is academically valuable in that it provides a high-resolution understanding of the plasticity of human brain immune cells in aging and AD progression. It presents a pathway in which cells in a homeostatic state transition to a protective GPNMB subtype in response to the disease, providing a basis for the discovery of therapeutic targets. This leads to the development of strategies that maximize the brain's inherent immune clearance capabilities, moving away from amyloid removal-centered therapies.

However, due to the nature of post-mortem tissue analysis, there is a limitation in that the dynamic changes of microglia cannot be directly observed in real time. There is also a challenge in that it is difficult to directly translate these findings to mouse models due to the differences between animal and human immune systems. Ultimately, in order to apply therapeutic agents targeting the MITF-GPNMB pathway clinically, a precise delivery technology is required to control off-target effects in other tissues.