Molecular cross talk between misfolded proteins in animal models of Alzheimer's and prion diseases.

The central event in protein misfolding disorders (PMDs) is the accumulation of a misfolded form of a naturally expressed protein. Despite the diversity of clinical symptoms associated with different PMDs, many similarities in their mechanism suggest that distinct pathologies may cross talk at the molecular level. The main goal of this study was to analyze the interaction of the protein misfolding processes implicated in Alzheimer's and prion diseases. For this purpose, we inoculated prions in an Alzheimer's transgenic mouse model that develop typical amyloid plaques and followed the progression of pathological changes over time. Our findings show a dramatic acceleration and exacerbation of both pathologies. The onset of prion disease symptoms in transgenic mice appeared significantly faster with a concomitant increase on the level of misfolded prion protein in the brain. A striking increase in amyloid plaque deposition was observed in prion-infected mice compared with their noninoculated counterparts. Histological and biochemical studies showed the association of the two misfolded proteins in the brain and in vitro experiments showed that protein misfolding can be enhanced by a cross-seeding mechanism. These results suggest a profound interaction between Alzheimer's and prion pathologies, indicating that one protein misfolding process may be an important risk factor for the development of a second one. Our findings may have important implications to understand the origin and progression of PMDs.

RESPIRATORY COMPENSATION MECHANISMS IN THE UPPER AND LOWER RESPIRATORY TRACTS OF AN ANIMAL MODEL AFTER SUBCHRONIC INHALATION EXPOSURE TO FORMALDEHYDE: IMPLICATIONS FOR TOXICOLOGY RISK ASSESSMENT (DEPOSITION, DOSE RECEIVED, RESPONSE)

The potential for significant human populations to experience long-term inhalation of formaldehyde and reports of symptomatology due to this exposure has led to a considerable interest in the toxicologic assessment of risk from subchronic formaldehyde exposures using animal models. Since formaldehyde inhalation depresses certain respiratory parameters in addition to its other forms of toxicity, there is a potential for the alteration of the actual dose received by the exposed individual (and the resulting toxicity) due to this respiratory effect. The respiratory responses to formaldehyde inhalation and the subsequent pattern of deposition were therefore investigated in animals that had received subchronic exposure to the compound, and the potential for changes in the formaldehyde dose received due to long-term inhalation evaluated. Male Sprague-Dawley rats were exposed to either 0, 0.5, 3, or 15 ppm formaldehyde for 6 hours/day, 5 days/week for up to 6 months. The patterns of respiratory response, deposition and the compensation mechanisms involved were then determined in a series of formaldehyde test challenges to both the upper and to the lower respiratory tracts in separate groups of subchronically exposed animals and age-specific controls (four concentration groups, two time points). In both the control and pre-exposed animals, there was a characteristic recovery of respiratory parameters initially depressed by formaldehyde inhalation to at or approaching pre-exposure levels within 10 minutes of the initiation of exposure. Also, formaldehyde deposition was found to remain very high in the upper and lower tracts after long-term exposure. Therefore, there was probably little subsequent effect on the dose received by the exposed individual that was attributable to the repeated exposures. There was a diminished initial minute volume response in test challenges of both the upper and lower tracts of animals that had received at least 16 weeks of exposure to 15 ppm, with compensatory increases in tidal volume in the upper tract and respiratory rate in the lower tract. However, this dose-related effect was probably not relevant to human risk estimation because this formaldehyde dose is in excess of that experienced by human populations. ^

Brain fiber tract plasticity in experimental spinal cord injury: diffusion tensor imaging.

Diffusion tensor imaging (DTI) and immunohistochemistry were performed in spinal cord injured rats to understand the basis for activation of multiple regions in the brain observed in functional magnetic resonance imaging (fMRI) studies. The measured fractional anisotropy (FA), a scalar measure of diffusion anisotropy, along the region encompassing corticospinal tracts (CST) indicates significant differences between control and injured groups in the 3 to 4 mm area posterior to bregma that correspond to internal capsule and cerebral peduncle. Additionally, DTI-based tractography in injured animals showed increased number of fibers that extend towards the cortex terminating in the regions that were activated in fMRI. Both the internal capsule and cerebral peduncle demonstrated an increase in GFAP-immunoreactivity compared to control animals. GAP-43 expression also indicates plasticity in the internal capsule. These studies suggest that the previously observed multiple regions of activation in spinal cord injury are, at least in part, due to the formation of new fibers.

In-vivo diffusion tensor imaging of rat spinal cord with a phased array coil at 7T

Magnetic resonance imaging (MRI) is a non-invasive technique that offers excellent soft tissue contrast for characterizing soft tissue pathologies. Diffusion tensor imaging (DTI) is an MRI technique that has shown to have the sensitivity to detect subtle pathology that is not evident on conventional MRI. ^ Rats are commonly used as animal models in characterizing the spinal cord pathologies including spinal cord injury (SCI), cancer, multiple sclerosis, etc. These pathologies could affect both thoracic and cervical regions and complete characterization of these pathologies using MRI requires DTI characterization in both the thoracic and cervical regions. Prior to the application of DTI for investigating the pathologic changes in the spinal cord, it is essential to establish DTI metrics in normal animals. ^ To date, in-vivo DTI studies of rat spinal cord have used implantable coils for high signal-to-noise ratio (SNR) and spin-echo pulse sequences for reduced geometric distortions. Implantable coils have several disadvantages including: (1) the invasive nature of implantation, (2) loss of SNR due to frequency shift with time in the longitudinal studies, and (3) difficulty in imaging the cervical region. While echo planar imaging (EPI) offers much shorter acquisition times compared to spin-echo imaging, EPI is very sensitive to static magnetic field inhomogeneities and the existing shimming techniques implemented on the MRI scanner do not perform well on spinal cord because of its geometry. ^ In this work, an integrated approach has been implemented for in-vivo DTI characterization of rat spinal cord in the thoracic and cervical regions. A three element phased array coil was developed for improved SNR and extended spatial coverage. A field-map shimming technique was developed for minimizing the geometric distortions in EPI images. Using these techniques, EPI based DWI images were acquired with optimized diffusion encoding scheme from 6 normal rats and the DTI-derived metrics were quantified. ^ The phantom studies indicated higher SNR and smaller bias in the estimated DTI metrics than the previous studies in the cervical region. In-vivo results indicated no statistical difference in the DTI characteristics of either gray matter or white matter between the thoracic and cervical regions. ^