Positron Emission Tomography in Animal Models of Tauopathies

Abstract

The microtubule-associated protein tau (MAPT) plays an important role in Alzheimer’s disease and primary tauopathy diseases. The abnormal accumulation of tau contributes to the development of neurotoxicity, inflammation, neurodegeneration, and cognitive deficits in tauopathy diseases. Tau synergically interacts with amyloid-beta in Alzheimer’s disease leading to detrimental consequence. Thus, tau has been an important target for therapeutics development for Alzheimer’s disease and primary tauopathy diseases. Tauopathy animal models recapitulating the tauopathy such as transgenic, knock-in mouse and rat models have been developed and greatly facilitated the understanding of disease mechanisms. The advance in PET and imaging tracers have enabled non-invasive detection of the accumulation and spread of tau, the associated microglia activation, metabolic, and neurotransmitter receptor alterations in disease animal models. In vivo microPET studies on mouse or rat models of tauopathy have provided significant insights into the phenotypes and time course of pathophysiology of these models and allowed the monitoring of treatment targeting at tau. In this study, we discuss the utilities of PET and recently developed tracers for evaluating the pathophysiology in tauopathy animal models. We point out the outstanding challenges and propose future outlook in visualizing tau-related pathophysiological changes in brain of tauopathy disease animal models.

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

“…For amyloid imaging, PET studies using [ 18 F]florbetapir [38][39][40][41], [ 18 F]florbetaben, [ 11 C]PIB [42,43], and and rTg4510 mice [31,32,[45][46][47][48][49][50][51], as well as [ 11 C]THK5317 [52] and [ 11 C]THK5117 [53], which bind to both tau and MAO-B, in double mutant TgF344 rats has been reported. We observed no change in the [ 18 F]PM-PBB3 SUVR in the hippocampus and cortex of APP/PS1 mice at 5 months.…”

Rapamycin Attenuated Zinc-Induced Tau Phosphorylation and Oxidative Stress in Rats: Involvement of Dual mTOR/p70S6K and Nrf2/HO-1 Pathways

“…The pathological level of zinc promotes tau tangle pathology in the brains of hAPP/htau (57) and tau mouse models (58). Tau transgenic mice are featured by synaptic dysfunction, neuronal loss, neuroinflammation, and impairment in white matter integrity associated with tau accumulation (59)(60)(61)(62)(63)(64). Abnormal accumulation of targeting metals has been shown to rescue the pathology and phenotype of transgenic mouse models of tauopathy (65).…”

Magnetic Resonance Imaging in Tauopathy Animal Models

“…Tau imaging has been even more challenging than amyloid imaging due to the intracellular location and size of tau aggregates, as well as the different tau isoforms ( Villemagne et al, 2015 ). Positron emission tomography (PET) imaging of tau in tauopathy mouse models using various tau-targeted radioligands has been established ( Maruyama et al, 2013 ; Brendel et al, 2016 ; Ono et al, 2017 ; Ishikawa et al, 2018 ; Ni et al, 2018 ; Tagai et al, 2020 ; Chaney et al, 2021 ; Cao et al, 2022 ). In addition, fluorescence imaging, two-photon microscopy, and photoacoustic imaging methods have been developed for in vivo mapping of tau accumulation in animal models ( Wu et al, 2018 ; Calvo-Rodriguez et al, 2019 ; Ni et al, 2020a ; Vagenknecht et al, 2021 ).…”