Abstract
The microtubule-associated protein tau plays an important role in tauopathic diseases such as Alzheimer’s disease and primary tauopathies such as progressive supranuclear palsy and corticobasal degeneration. Tauopathy animal models, such as transgenic, knock-in mouse and rat models, recapitulating tauopathy have facilitated the understanding of disease mechanisms. Aberrant accumulation of hyperphosphorylated tau contributes to synaptic deficits, neuroinflammation, and neurodegeneration, leading to cognitive impairment in animal models. Recent advances in molecular imaging using positron emission tomography (PET) and magnetic resonance imaging (MRI) have provided valuable insights into the time course of disease pathophysiology in tauopathy animal models. High-field MRI has been applied for in vivo imaging in animal models of tauopathy, including diffusion tensor imaging for white matter integrity, arterial spin labeling for cerebral blood flow, resting-state functional MRI for functional connectivity, volumetric MRI for neurodegeneration, and MR spectroscopy. In addition, MR contrast agents for non-invasive imaging of tau have been developed recently. Many preclinical MRI indicators offer excellent translational value and provide a blueprint for clinical MRI in the brains of patients with tauopathies. In this review, we summarized the recent advances in using MRI to visualize the pathophysiology of tauopathy in small animals. We discussed the outstanding challenges in brain imaging using MRI in small animals and propose a future outlook for visualizing tau-related alterations in the brains of animal models.
Highlights
Six microtubule-associated protein tau (MAPT) isoforms are expressed in the adult human brain and are further categorized into 4-repeat (4R) and 3-repeat (3R) species (Lee et al, 2001)
There has been a rapid development in magnetic resonance imaging (MRI) technology in recent years, in high-field MR scanners
7, 9.4, 11.7, 16, and up to 21.1 T high-field MRI has been utilized in the laboratory (Schepkin et al, 2010; Miyaoka and Lehnert, 2020; Ni, 2021), providing insights into the function and pathophysiology of the brain
Summary
Six microtubule-associated protein tau (MAPT) isoforms are expressed in the adult human brain and are further categorized into 4-repeat (4R) and 3-repeat (3R) species (Lee et al, 2001). Animal models exhibit tau accumulation, neuroinflammation, synaptic dysfunction, brain regional atrophy, and cognitive impairment to different extents (Götz et al, 2018; Ishikawa et al, 2018; Ising et al, 2019). Magnetic resonance imaging (MRI) has been widely used to non-invasively probe the tissue changes associated with cerebral tau pathology in patients with AD and FTD (Du et al, 2006; Boxer et al, 2020; Young et al, 2021). Pathological tau accumulates mainly in excitatory neurons rather than in inhibitory neurons, leading to neuronal network dysfunction and neural circuit impairment (Busche et al, 2008; Fu et al, 2019) Functional imaging techniques, such as manganese-enhanced MRI (MEMRI), ASL, restingstate functional MRI (rs-fMRI), and contrast-enhanced fMRI, have been widely used to probe brain functional alterations in small animals. Degiorgis et al (2020) demonstrated that there was hyperactivated functional connectivity in the hippocampus, amygdala, and isocortical areas in Thy-Tau mice at an early stage (5 months of age) compared with wild-type mice
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