Abstract
Proton magnetic resonance spectroscopy (1H-MRS) has been used to provide useful information about the neurochemical changes reflecting early pathological alterations in Alzheimer's disease (AD) brain. In this study, we have longitudinally measured the hippocampal neurochemical profile in vitro in senescent mice induced with chronic injection of D-Galactose and NaNO2, at different time point from day 30 to day 70 with a 10-day interval. Pathological brain alterations induced by D-Galactose and NaNO2 were monitored through hematoxylin and eosin (HE) staining, Congo red staining and bielschowsky silver staining, and the cognition deficits were assessed via Morris Water Maze (MWM) test. This D-galactose and NaNO2 treated mouse model, characterized by an early-onset memory dysfunction, a robust neuronal loss, amyloid plaques and neurofibrillary tangles in hippocampal subdivision, well mimics a prodromal Alzheimer's phenotype. Consistent with previously published in vivo 1H MRS findings in human AD patients and AD transgenic mice, our in vitro 1H MRS on the perchloric acid extractions of hippocampus in senescent mice observed significant decreases of N-acetylaspartate (NAA) and Glutamate (Glu) but an increase in Myo-inositol (mIns). Elevated mIns occurred prior to the reduction of NAA and Glu during the progression of aging. In addition, changes in mIns, NAA and Glu were found to precede pathological abnormalities. Overall, our in vitro findings in senescent mice validated the concept that hippocampal neurochemical alternations preceded the pathological changes of the brain, and could serve as potential markers of AD progression. Reductions of NAA and Glu can be interpreted in terms of neuronal degeneration and dysfunctions in glutamatergic activity that may contribute to the pathophysiological mechanisms underlying AD. Elevated mIns might be related to glial activation. Further experiments are needed to explore the potential value of mIns in the early diagnosis of AD, to verify whether glial cell proliferation occurs earlier than neuronal changes.
Highlights
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, has become a major public health concern in societies with aging populations [1,2,3]
Medical treatment is effective only for patients with pre-symptomatic AD and mild cognitive impairment (MCI) in the prodromal stage, who have not yet presented irreversible neuronal changes [4], and only early medical intervention may delay the progression of AD and improve the patient’s quality of life
Transgenic mouse models, most of which were based on the overexpression of mutated forms of human amyloid-b protein precursor (AbPP) or in combination with mutated human presenilin 1 (PS1) or 2 (PS2) genes [28], reproduced the histopathological features of AD
Summary
Alzheimer’s disease (AD), a progressive neurodegenerative disorder, has become a major public health concern in societies with aging populations [1,2,3]. There is considerable value to identify disease-specific markers for AD progression which would aid in early diagnosis, drug development and therapeutic monitoring. Neuroimaging has been used to investigate morphological abnormalities (such as MRI-based volumetric measurement of hippocampus [5,6], amyloid plaques imaging [7,8,9]) and neurochemical alterations [10,11,12,13,14] in clinical AD brains during disease progressions. AD-related neurochemical alterations were found to precede morphological changes (reviewed in [15]), and were regarded as plausible markers of the pathological progression in AD. Proton magnetic resonance spectroscopy (1HMRS) is a powerful tool for assessing the metabolic and biochemical changes of living tissues as well as quantitative analyses of compounds [16,17,18], bringing hope for early detection of AD.
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