Anatomical and Functional Phenotyping of Mice Models of Alzheimer's Disease by MR Microscopy

Abstract

The wide variety of transgenic mouse models of Alzheimer's disease (AD) reflects the search for specific genes that influence AD pathology and the drive to create a clinically relevant animal model. An ideal AD mouse model must display hallmark AD pathology such as amyloid plaques, neurofibrillary tangles, reactive gliosis, dystrophic neurites, neuron and synapse loss, and brain atrophy and in parallel behaviorally mimic the cognitive decline observed in humans. Magnetic resonance (MR) microscopy (MRM) can detect amyloid plaque load, development of brain atrophy, and acute neurodegeneration. MRM examples of AD pathology will be presented and discussed. What has lagged behind in preclinical research using transgenic AD mouse models is functional phenotyping of the brain; in other words, the ability to correlate a specific genotype with potential aberrant brain activation patterns. This lack of information is caused by the technical challenges involved in performing functional MRI (fMRI) in mice including the effects of anesthetic agents and the lack of relevant "cognitive" paradigms. An alternative approach to classical fMRI using external stimuli as triggers of brain activation in rodents is to electrically or pharmacologically stimulate regions directly while simultaneously locally tracking the activated interconnected regions of rodents using, for example, the manganese-enhanced MRI (MEMRI) technique. Finally, transgenic mouse models, MRM, and future AD research would be strengthened by the ability to screen for AD-like pathology in other non-AD transgenic mouse models. For example, molecular biologists may focus on cardiac or pulmonary pathologies in transgenic mice models and as an incidental finding discover behavioral AD phenotypes. We will present MRM data of brain and cardiac phenotyping in transgenic mouse models with behavioral deficits.

APP Transgenic Mice: Their Use and Limitations

“…PDAPP mice were also investigated longitudinally over 22 months by Benveniste et al (2007) using diffusion-weighted MRI. No whole brain atrophy was found either at 9 months, when plaques start to be detectable in this mouse model (Games et al 1995;Irizarry et al 1997b), or at 22 months.…”

Novel frontiers in ultra-structural and molecular MRI of the brain

“…For example iron-laden plaques associated with AD have been detected in the hippocampus in ex-vivo human tissue [40] and in-vivo in mouse models [41]. In addition, changes in T 2 * relaxation characteristics may be indicative of myelin loss and therefore be valuable in characterizing demyelinating diseases such as MS and Adrenoleukodystrophy (ALD) [42–45…”

Should we enhance animals?

“…Transgenic mice bearing introduced genes7 from humans or other species are commonly used in biomedical research—for example, genes for the various proteins implicated in Alzheimer’s disease to create a mouse model to study disease pathology8 or human immunological genes to create a mouse with a “humanised” immune system 9. Another, perhaps more frivolous, example is ornamental fish that have been genetically modified to display fluorescent colouration 10…”