Monitoring disease progression in transgenic mouse models of Alzheimer's disease with proton magnetic resonance spectroscopy

Abstract

Currently no definitive biomarker of Alzheimer's disease (AD) is available, and this impedes both clinical diagnosis in humans and drug discovery in transgenic animal models. Proton magnetic resonance spectroscopy ( 1 H MRS) provides a noninvasive way to investigate in vivo neurochemical abnormalities. Each observable metabolite can potentially provide information about unique in vivo pathological processes at the molecular or cellular level. In this study, the age-dependent 1 H MRS profile of transgenic AD mice was compared to that of wild-type mice. Twenty-seven APP-PS1 mice (which coexpress mutated human presenilin 1 and amyloid-␤ precursor protein) and 30 wild-type mice age 66 -904 days were examined, some repeatedly. A reduction in the levels of N-acetylaspartate and glutamate, compared with total creatine levels, was found in APP-PS1 mice with advancing age. The most striking finding was a dramatic increase in the concentration of myo-inositol with age in APP-PS1 mice, which was not observed in wild-type mice. The age-dependent neurochemical changes observed in APP-PS1 mice agree with results obtained from in vivo human MRS studies. Among the different transgenic mouse models of AD that have been studied with 1 H MRS, APP-PS1 mice seem to best match the neurochemical profile exhibited in human AD. 1 H MRS could serve as a sensitive in vivo surrogate indicator of therapeutic efficacy in trials of agents designed to reduce neurotoxicity due to microglial activation. Because of its noninvasive and repeatable nature, MRS in transgenic models of AD could substantially accelerate drug discovery for this disease.myo-inositol ͉ taurine ͉ drug discovery P roton magnetic resonance spectroscopy ( 1 H MRS) provides a noninvasive way to investigate in vivo neurochemical abnormalities of many brain disorders. In particular, MRS is particularly well suited for the study of neurodegenerative disorders, because no biomarkers for such disorders currently exist. Each observable metabolite can potentially provide unique information about the degenerative process, because metabolite levels are sensitive to different in vivo pathological processes at the molecular or cellular level. For example, N-acetylaspartate (NAA) is believed to be a marker for neuronal number and health, glutamate (Glu) acts as an excitatory neurotransmitter, and myo-inositol (mIns) is thought to be a marker for osmotic stress or astrogliosis.Alzheimer's disease (AD) is the most common cause of dementia in the elderly. The primary risk factor for AD is age. As the population of virtually all modern industrialized societies ages, AD is poised to become a leading public health problem. The vast majority of prevalent cases of AD are sporadic. The remaining few percent of familial cases are attributed to specific mutations. Three known classes of mutations are associated with familial AD. Although statistically uncommon, the genetic associations with familial AD have shed insight into the origins of the disease. It is believed by many in the field that AD is ...

The neurochemical profile quantified by in vivo 1H NMR spectroscopy

“…Dedeoglu et al (2004) but not Marjanska et al (2005) reproduced these findings in mice possessing only the mutated APP gene. Both authors reported, however, higher cerebral taurine to creatine ratio in the brain of APP transgenic mice compared to wild type mice (Dedeoglu et al, 2004;Marjanska et al, 2005). These results were confirmed by in vitro NMR spectroscopy of brain extracts, in which glutathione levels were additionally found to be lower than in controls (Dedeoglu et al, 2004).…”

“…Additionally, it was found that once amyloid plaques are observed, NAA levels are inversely associated to the area of cortex occupied by plaques (Choi et al, 2010). Dedeoglu et al (2004) but not Marjanska et al (2005) reproduced these findings in mice possessing only the mutated APP gene. Both authors reported, however, higher cerebral taurine to creatine ratio in the brain of APP transgenic mice compared to wild type mice (Dedeoglu et al, 2004;Marjanska et al, 2005).…”

“…Double transgenic mice expressing human mutant APP and human mutated PS1 (APP/PS1) display decreased glutamate and NAA concentrations in the brain, particularly in the hippocampus, that were observed at the time where hippocampal volume was already reduced but amyloid plaques were not yet present (Choi et al, 2010;Marjanska et al, 2005;Oberg et al, 2008). Later, upon visible amyloid deposits, these mice also presented increased brain myo-inositol to creatine ratio, when compared to wild type mice , accompanied by astrogliosis as detected by histochemistry methods .…”

Metabolic properties in stroked rats revealed by relaxation-enhanced magnetic resonance spectroscopy at ultrahigh fields

“…MRS thus can report about neurotransmitters (glutamate, aspartate and gaminobutyric acid), bioenergetic metabolites (creatines (Cre), lactic acid (Lac)) and osmolytes (N-acetyl-asparate (NAA)), molecules involved with membrane synthesis (cholines (Cho)), sugars (glucose, inositols) and other CNS metabolites present at millimolar concentrations 14,15 . MRS has afforded valuable insights into the nature of disease metabolism [16][17][18] ; furthermore, since some of these metabolites are selectively compartmentalized, for example, NAA is considered intraneuronal, whereas myo-inositols reside mostly in astrocytes, MRS can potentially resolve structurally distinct cellular environs.…”

In Vivo mouse imaging and spectroscopy in drug discovery

“…Despite the practical challenges in performing MRS studies in living mice [see refs (82)(83)(84) for reviews], several groups have shown the feasibility of performing spectroscopic assessments in a routine manner. Areas of application in mice include neurosciences (85)(86)(87), cardiac (88) and musculoskeletal diseases (89,90), and cancer (91)(92)(93)(94). The use of high field strengths (9.4 T) in conjunction with advanced shim capabilities has allowed the acquisition of high-resolution proton spectra from the mouse brain (95,96).…”