Faculty Bibliography

The presence of amyloid-beta (Abeta) plaques in the brain is a hallmark pathological feature of Alzheimer's disease (AD). Transgenic mice overexpressing mutant amyloid precursor protein (APP), or both mutant APP and presenilin-1 (APP/PS1), develop Abeta plaques similar to those in AD patients, and have been proposed as animal models in which to test experimental therapeutic approaches for the clearance of Abeta. However, at present there is no in vivo whole-brain imaging method to detect Abeta plaques in mice or men. A novel method is presented to detect Abeta plaques in the brains of transgenic mice by magnetic resonance microimaging (muMRI). This method uses Abeta1-40 peptide, known for its high binding affinity to Abeta, magnetically labeled with either gadolinium (Gd) or monocrystalline iron oxide nanoparticles (MION). Intraarterial injection of magnetically labeled Abeta1-40, with mannitol to transiently open the blood-brain barrier (BBB), enabled the detection of many Abeta plaques. Furthermore, the numerical density of Abeta plaques detected by muMRI and by immunohistochemistry showed excellent correlation. This approach provides an in vivo method to detect Abeta in AD transgenic mice, and suggests that diagnostic MRI methods to detect Abeta in AD patients may ultimately be feasible

Signal abnormalities on magnetic resonance imaging (MRI) T2-weighted images (T2WI) have been described in patients with Creutzfeldt-Jakob disease; however, the pathology underlying these findings remains to be fully described. We investigated the time-course of signal alterations in a murine model of prion disease using in vivo 9.4 Tesla micro magnetic resonance imaging (muMRI). The topography of muMRI signal changes was correlated with the accumulation of proteinase resistant PrP(Sc) in corresponding brain sections. Increased signal intensity on T2WI was observed in the septum and in the hippocampus of presymptomatic mice 120 days post infection (dpi). Mildly symptomatic animals (150 dpi) and animals with apparent neurological deficit (180 dpi) had a greater increase of signal intensity on T2WI in the septum and the hippocampus; in addition, abnormalities in the cortex and in the thalamus were found. Neuropathological evaluation demonstrated accumulation of PrP(Sc) and astrogliosis but only minimal or no spongiform changes in structures where abnormal signal was detected. These observations suggest that early pathological changes related to the accumulation of PrP(Sc) may be detectable in presymptomatic subjects using MRI systems with higher magnetic field strength

A significant percentage of Alzheimer's disease (AD) patients exhibit concomitant vascular pathology. Epidemiological evidence suggest that vascular disease may not only add to global cognitive impairment but also exacerbate the course of AD pathology. The goal of this study was to analyze the impact of global ischemia on the cellular and amyloid-beta pathology in AD murine transgenic (Tg) models. Seven month old double Tg mice, expressing Swedish amyloid precursor protein (APP) and M146L presenilin 1 (PS1) mutations and single Tg mice (PS1 mutation alone) were subjected to 45 minutes bilateral common carotid artery occlusion or sham surgery. Behavioral testing performed two weeks after the surgery showed impaired learning and memory retention on Morris water maze and Hebb-Williams tests in both single PS1 and double PS1/APP Tg mice which underwent ischemia comparing to sham operated animals (p<0.05). Double Tg mice scored worse than single Tg mice. Animals were sacrificed two months after ischemia. The total brain volume was decreased by 6.5% and 5% and the ventricular volume was increased by 33.7% and 46.4% in single and double operated Tg mice, respectively comparing to sham animals. Unbiased stereological analysis demonstrated a 23% neuronal dropout in the CA1 sector of the cornu Ammonis after ischemia. Increased Abetaburden and plaque density was also observed in APP/PS1 animals which underwent ischemia comparing to sham operated ones. Overall, this data indicate that global ischemia exacerbate both neuronal and Abetarelated pathology in AD Tg animal models