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Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Alzheimer's disease (AD) treatments include anti-amyloid beta (Aß) immunotherapies.
  • These therapies can cause Amyloid-Related Imaging Abnormalities (ARIA), such as cerebral edema (ARIA-E) or hemorrhages (ARIA-H).
  • Neuroinflammation, particularly at the neurovascular unit, is implicated in ARIA development.

Purpose of the Study:

  • To investigate if inhibiting soluble TNFα (sTNFα) alongside Aß immunotherapy can reduce systemic inflammation and ARIA-H.
  • To test the hypothesis that combining sTNFα inhibition with Aß immunotherapy mitigates ARIA-H.

Main Methods:

  • Utilized aged APP-knockin mice treated with an Aß-targeting antibody (3D6) and an sTNFα inhibitor or saline for 3 months.
  • Quantified amyloid burden using Congo red staining.
  • Assessed systemic inflammation via platelet activation using flow cytometry and microhemorrhage occurrence using Prussian blue staining.

Main Results:

  • 3D6 treatment increased bleeding in the cortex and hippocampus compared to controls.
  • sTNFα inhibition significantly reduced 3D6-induced hippocampal bleeds.
  • sTNFα inhibition also prevented the increased platelet activation observed in 3D6-treated mice.

Conclusions:

  • Inhibition of sTNFα shows promise as an adjunct therapy to anti-Aß antibodies.
  • This combination may reduce systemic inflammation and the development of microhemorrhages (ARIA-H).
  • Further research into sTNFα as a therapeutic target for ARIA-H is warranted.