Relationship between reactive astrocytes, by [¹⁸F]SMBT-1 imaging, with amyloid-beta, tau, glucose metabolism, and microgliosis in mouse models of Alzheimer’s disease

Abstract

PurposeReactive astrocytes play an important role in the development of Alzheimer’s disease (AD). Here, we aim to investigate the temporospatial relationship between reactive astrocytes, tau and amyloid-β, glucose metabolism, and microgliosis by using multitracer imaging in AD transgenic mouse models.MethodsPositron emission tomography (PET) imaging with [18F]SMBT-1 (monoamine oxidase-B), [18F]florbetapir (Aβ), [18F]PM-PBB3 (tau), [18F]FDG, and [18F]DPA-714 (translocator protein) was carried out in 5- and 10-month-old APP/PS1, 11-month-old 3×Tg mice, and aged-matched wild-type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as the reference region. Immunofluorescence staining was performed in mouse brain tissue slices.Results[18F]SMBT-1 and [18F]florbetapir SUVRs were higher in the cortex and hippocampus of 10-month-old APP/PS1 mice than in 5-month-old APP/PS1 mice and wild-type mice. Reduced [18F]FDG SUVR was observed in the thalamus and midbrain of 5-month-old APP/PS1 mice compared to wild-type mice. No significant difference in brain regional [18F]DPA-714 SUVR was observed in 5- and 10-month-old APP/PS1 mice compared to wild- type mice. No significant difference in the SUVRs of any tracers was observed in 11-month-old 3×Tg mice compared to age-matched wild-type mice. A positive correlation between the SUVRs of [18F]SMBT-1 and [18F]DPA-714 in the cortex was observed. Immunostaining validated the distribution of MAO-B and TSPO, amyloid and tau inclusions in brain tissue from 10-month-old APP/PS1 mice and limited changes in 11-month- old 3×Tg mice.ConclusionThe findings provide in vivo evidence for reactive astrocytes along with amyloid plaque and tau deposition preceding microgliosis in animal models of AD pathologies.

Hippocampal purinergic P2X7 receptor level is increased in Alzheimer’s disease patients, and associated with amyloid and tau pathologies

“…Two 27-month-old 3×Tg mice [B6;129-Psen1tm1MpmTg (APPSwe, tauP301L)1Lfa/Mmjax] from the Jackson Laboratory (USA) and two age-matched wild-type mice were used (36, 47). Animals were housed in ventilated cages inside a temperature-controlled room under a 12-h dark/light cycle.…”

Hippocampal mGluR5 levels are comparable in Alzheimer’s and control brains, and divergently influenced by amyloid and tau in control brain

“…Six 3×Tg mice [B6;129-Psen1tm1MpmTg(APPSwe, tauP301L)1Lfa/Mmjax] were purchased from Jax Laboratory (33,36). Ten arcAβ transgenic mice (human APP695 transgenes harboring Swedish and Arctic (E693G) mutations under the control of the prion protein promoter) (30,56) and eight nontransgenic littermates were used.…”