Atkinson, J. R. | Search bioRxiv

bioRxiv2026

A self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer's disease

Microglia are key drivers of Alzheimer's disease (AD), and TREM2, one of the strongest genetic risk factors, enables the disease-associated microglia (DAM) state required for plaque engagement. How TREM2 sustains this protection, and why it falters as disease advances, remain unclear. Using proteomics, single-cell transcriptomics, and in vivo metabolic labeling, we show that plaque-associated microglia mount a TREM2-dependent anabolic program coupling nascent protein synthesis to mitochondrial biogenesis. This program, not the DAM signature, marks phagocytically competent microglia; its loss is associated with proteostatic overload and mitochondrial dysfunction. Unexpectedly, this anabolic program is self-limiting, peaking at low amyloid burden and declining as burden rises. This decline is conserved in humans: across 523 donors, anabolic capacity tracks TREM2 but falls at advanced Braak stage even as DAM signature keeps rising. Thus, anabolic capacity, rather than activation state, marks microglial resilience in AD, and sustained stimulation of phagocytosis by anti-amyloid antibodies risks biosynthetic exhaustion and self-limiting efficacy.

neuroscience↗

bioRxiv2021

Biological Aging of CNS-Resident Cells Alters the Clinical Course and Immunopathology of Autoimmune Demyelinating Disease

Biological aging is the strongest factor associated with the clinical phenotype of multiple sclerosis (MS). Relapsing remitting MS (RRMS) typically presents in the third or fourth decade, while the mean age of presentation of progressive MS (pMS) is 45 years old. Here we show that experimental autoimmune encephalomyelitis (EAE), induced by the adoptive transfer of encephalitogenic CD4+ Th17 cells, is more severe, and less like to remit, in middle-aged compared with young adult mice. Donor T cells and neutrophils are more abundant, while B cells are relatively sparse, in central nervous system (CNS) infiltrates of the older mice. Experiments with reciprocal bone marrow chimeras demonstrate that radio-resistant, non-hematopoietic cells play a dominant role in shaping age-dependent features of the neuroinflammatory response, as well as the clinical course, during EAE. Reminiscent of pMS, EAE in middle-aged adoptive transfer recipients is characterized by widespread microglial activation. Microglia from older mice express a distinctive transcriptomic profile, suggestive of enhanced chemokine synthesis and antigen presentation. Collectively, our findings suggest that drugs that suppress microglial activation, and acquisition or expression of aging-associated properties, may be beneficial in the treatment of progressive forms of inflammatory demyelinating disease.

neuroscience↗