A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2) Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases. VIDEO ABSTRACT.

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Paradoxically, microglia impairment might be sustained by inflammatory cytokines, which suggests that AD pathology can be accelerated through this vicious circle (Heppner et al, 2015). A recent single‐cell RNA‐Seq study in an AD mouse model identified a novel microglia subtype which is AD‐associated phagocytic cell conserved in mice and human (Keren‐Shaul et al, 2017). A list of attractive immune targets has been regarded as having therapeutic values (Heppner et al, 2015).…”

The immunogenetics of neurological disease

“…The roles of microglia in several neurological diseases are well documented. [26][27][28] Taken together, the HLA loci are vital for shaping cellular adaptive immune responsiveness, and their impact upon human health and disease has long been appreciated. During the course of four decades, the impact of variation in HLA has been studied with respect to neurological disease.…”

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

“…More interesting, recent studies found a novel microglia cell type associated with neurodegenerative diseases (DAM cells) using single‐cell RNA‐seq technology, which displayed a unique capability to clear Aβ (Keren‐Shaul, Spinrad, Weiner, Matcovitch‐Natan, & Dvir‐Szternfeld, 2017). Furthermore, another group also found glial cells in patients with AD bearing TREM2 variants, and Trem2 ‐deficient mice have a greater abundance of autophagic vesicle accumulation and an AD‐like pathology (Ulland, Song, Huang, Ulrich, & Sergushichev, 2017).…”