Pre-therapeutic microglia activation and sex determine therapy effects of chronic immunomodulation

Theranostics. 2021 Aug 19;11(18):8964-8976. doi: 10.7150/thno.64022. eCollection 2021.

Abstract

Modulation of the innate immune system is emerging as a promising therapeutic strategy against Alzheimer's disease (AD). However, determinants of a beneficial therapeutic effect are ill-understood. Thus, we investigated the potential of 18 kDa translocator protein positron-emission-tomography (TSPO-PET) for assessment of microglial activation in mouse brain before and during chronic immunomodulation. Methods: Serial TSPO-PET was performed during five months of chronic microglia modulation by stimulation of the peroxisome proliferator-activated receptor (PPAR)-γ with pioglitazone in two different mouse models of AD (PS2APP, AppNL-G-F ). Using mixed statistical models on longitudinal TSPO-PET data, we tested for effects of therapy and sex on treatment response. We tested correlations of baseline with longitudinal measures of TSPO-PET, and correlations between PET results with spatial learning performance and β-amyloid accumulation of individual mice. Immunohistochemistry was used to determine the molecular source of the TSPO-PET signal. Results: Pioglitazone-treated female PS2APP and AppNL-G-F mice showed attenuation of the longitudinal increases in TSPO-PET signal when compared to vehicle controls, whereas treated male AppNL-G-F mice showed the opposite effect. Baseline TSPO-PET strongly predicted changes in microglial activation in treated mice (R = -0.874, p < 0.0001) but not in vehicle controls (R = -0.356, p = 0.081). Reduced TSPO-PET signal upon pharmacological treatment was associated with better spatial learning despite higher fibrillar β-amyloid accumulation. Immunohistochemistry confirmed activated microglia to be the source of the TSPO-PET signal (R = 0.952, p < 0.0001). Conclusion: TSPO-PET represents a sensitive biomarker for monitoring of immunomodulation and closely reflects activated microglia. Sex and pre-therapeutic assessment of baseline microglial activation predict individual immunomodulation effects and may serve for responder stratification.

Keywords: AppNL-G-F mice; PS2APP mice; TSPO-PET; microglia; pioglitazone; prediction; sex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Disease Models, Animal
  • Female
  • Immunity, Innate / immunology
  • Immunomodulation / immunology
  • Immunomodulation / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism*
  • PPAR gamma / drug effects
  • PPAR gamma / metabolism
  • Pioglitazone / pharmacology
  • Positron-Emission Tomography / methods
  • Receptors, GABA / metabolism*
  • Receptors, GABA / physiology
  • Sex Factors

Substances

  • Amyloid beta-Peptides
  • Bzrp protein, mouse
  • PPAR gamma
  • Receptors, GABA
  • Pioglitazone