The Generative Brain

Downstream glial and neuroinflammation targets

Instead of lowering the prion protein, this idea targets the brain's own support cells that react to prion damage. Microglia and astrocytes seem to protect early and cause harm when activated for too long, so the open problem is which state to push and when. The clearest warning from mouse work is that removing microglia made prion disease faster, so the target is a specific state, not microglia in general. One lead is GPNMB, a protein on a late-appearing microglial state that is raised in mice and in sporadic CJD samples; a CRISPR screen funded by the CJD Foundation is looking for ways to raise it earlier. No glial drug has shown benefit in prion animals in the sources read. Information only.

Key facts

  • Framing in a 2026 review: glia are protective early and maladaptive when activation is sustained, microglia and astrocytes influence each other, and prion disease is multifactorial so combinations may be needed.
  • Microglia depletion makes mouse prion disease worse: oral PLX5622 removed 78 to 90 percent of cortical microglia, mice needed euthanasia 31 days earlier when started soon after infection and 33 days earlier when started at 80 days, and ME7 and 22L strains were also faster.
  • The authors of that study read this as microglia clearing PrPSc and suggest drugs boosting helpful microglial activity could slow disease; the abstract notes older CSF-1R studies disagreed because depletion was patchy.
  • A 2025 preprint finds a Gpnmb-positive microglial subset that appears late (from about 30 weeks after infection in RML6-infected mice) in regions with excitatory neuron loss, strongest in thalamus.
  • The same preprint reports higher GPNMB mRNA in prefrontal cortex of 5 sporadic CJD patients versus 5 matched controls and higher shed GPNMB in CSF (not serum) in infected mice and sCJD patients; group sizes are small.
  • Cell experiments point to signals from dying cells, not prions, as the trigger, and full loss of Gpnmb in a microglial cell line reduced uptake of apoptotic cells; the authors say a causal link to neuron loss is not yet shown in animals.
  • A University of Zurich news item (May 2026) describes a Nature Communications paper involving the Polymenidou lab with the same message: a Gpnmb-positive phagocytic microglial state tied to cell death, seen also in human cell models, stroke models and sCJD samples, with GPNMB suggested as a marker of neurodegeneration.
  • Funding: a 2024 CJD Foundation grant to Aguzzi and Caredio (University of Zurich) to find genes that raise GPNMB in human microglia by a CRISPR activation screen, then test hits in better models; the grantees say GPNMB rises mainly late and protected tissue from prions in the lab, which is their own statement and not peer reviewed.
  • Safety and limits: the PLX5622 result shows broad microglia removal is harmful in this model; the GPNMB work is correlative in animals and human samples and the preprint calls in vivo causality open; no toxicity or dosing data exist for any glial candidate in the sources read.
  • Human data: expression and CSF measurements in a small number of autopsy and CSF samples; no treatment data.

Timeline

  1. 2018Journal of Virology study: PLX5622 microglia depletion speeds scrapie disease in mice.
  2. 2024CJD Foundation grant page for the GPNMB target-discovery project published.
  3. 2025Preprint on Gpnmb-positive microglia in prion disease (date from the preprint identifier).
  4. 2026Frontiers review (final search 7 April 2026) says glial modulation is underdeveloped and combinations may be needed.
  5. 2026Zurich news item on a Nature Communications paper on a Gpnmb-positive microglial state in prion and other models.
Sources for this page