RESUMO
Transgenic animal models of Alzheimer's disease (AD) can mimic pathological and behavioral changes occurring in AD patients, and are usually viewed as the first choice for testing novel therapeutics. Validated biomarkers, particularly non-invasive ones, are urgently needed for AD diagnosis or evaluation of treatment results. However, there are few studies that systematically characterize pathological changes in AD animal models. Here, we investigated the brain of 8-month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic and wild-type (WT) mice, employing 7.0-T magnetic resonance imaging (MRI). Magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) were obtained through micro-MRI scanning. After MRI examination in both transgenic (nâ¯=â¯12) and WT (nâ¯=â¯12) mice, immunohistochemical staining and ultrastructural analysis were subsequently performed. Cerebral blood flow (CBF) was significantly decreased in the left hippocampus, left thalamus, and right cortex of AD mice (Pâ¯<â¯0.05). Moreover, MRS showed significantly changed NAA/Cr, Glu/Cr, and mI/Cr ratios in the hippocampus of transgenic mice. While only NAA/Cr and mI/Cr ratios varied significantly in the cortex of transgenic mice. Regarding DTI imaging, however, the values of FA, MD, DA and DR were not significantly different between transgenic and WT mice. Finally, it is worth noting that pathological damage of metabolism, CBF, and white matter was more distinct between transgenic and WT mice by pathological examination. Altogether, our results suggest that intravital imaging evaluation of 8-month-old APP/PS1 transgenic mice by MRS and ASL is an alternative tool for AD research.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Modelos Animais de Doenças , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Artérias/patologia , Biomarcadores/metabolismo , Encéfalo/metabolismo , Circulação Cerebrovascular , Imagem de Tensor de Difusão/métodos , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Hipocampo/metabolismo , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Camundongos , Camundongos Transgênicos , Presenilina-1/genética , Presenilina-1/metabolismo , Marcadores de SpinRESUMO
Our original findings, showing the effectiveness of active and passive tau immunizations in mouse models, have now been confirmed and extended by many groups, with several clinical trials underway in Alzheimer's disease and progressive supranuclear palsy. Here, we report on a unique and sensitive two-photon imaging approach to concurrently study the dynamics of brain and neuronal uptake and clearance of tau antibodies as well as the acute removal of their pathological target in live animals. This in vivo technique is more sensitive to detect clearance of pathological tau protein than western blot tau analysis of brain tissue. In addition to providing an insight into the mechanisms involved, it allows for an efficient in vivo assessment of the therapeutic potential of tau antibodies, and may be applied to related protein misfolding diseases.