A Preclinical Assessment of Neural Stem Cells as Delivery Vehicles for Anti-Amyloid Therapeutics

Transplantation of neural stems cells (NSCs) could be a useful means to deliver biologic therapeutics for late-stage Alzheimer's disease (AD). In this study, we conducted a small preclinical investigation of whether NSCs could be modified to express metalloproteinase 9 (MMP9), a secreted protease reported to degrade aggregated Aβ peptides that are the major constituents of the senile plaques. Our findings illuminated three issues with using NSCs as delivery vehicles for this particular application. First, transplanted NSCs generally failed to migrate to amyloid plaques, instead tending to colonize white matter tracts. Second, the final destination of these cells was highly influenced by how they were delivered. We found that our injection methods led to cells largely distributing to white matter tracts, which are anisotropic conduits for fluids that facilitate rapid distribution within the CNS. Third, with regard to MMP9 as a therapeutic to remove senile plaques, we observed high concentrations of endogenous metalloproteinases around amyloid plaques in the mouse models used for these preclinical tests with no evidence that the NSC-delivered enzymes elevated these activities or had any impact. Interestingly, MMP9-expressing NSCs formed substantially larger grafts. Overall, we observed long-term survival of NSCs in the brains of mice with high amyloid burden. Therefore, we conclude that such cells may have potential in therapeutic applications in AD but improved targeting of these cells to disease-specific lesions may be required to enhance efficacy

Assessment of Fluid Cavitation Threshold Using a Polymeric Split Hopkinson Bar-Confinement Chamber Apparatus

The authors would like to acknowledge the Natural Sciences and Engineering Research Council of Canada for financial support, and Compute Canada and Sharcnet for providing the necessary computing resources.Mild Traumatic Brain Injury (mTBI) has been associated with blast exposure resulting from the use of improvised explosive devices (IEDs) in recent and past military conflicts. Experimental and numerical models of head blast exposure have demonstrated the potential for high negative pressures occurring within the head at the contre-coup location relative to the blast exposure, and it has been hypothesized that this negative pressure could result in cavitation of Cerebrospinal Fluid (CSF) surrounding the brain, leading to brain tissue damage. The cavitation threshold of CSF, the effect of temperature, and the effect of impurities or dissolved gases are presently unknown. In this study, a novel Polymeric Split Hopkinson Pressure Bar and confinement chamber apparatus were used to generate loading in distilled water similar to the conditions in the vicinity of the CSF during blast exposure. Cavitation was identified using high-speed imaging of the event, and a validated numerical model of the apparatus was applied to determine the pressure in the fluid during the exposure. Increasing the water temperature resulted in a decrease in the 50% probability of cavitation from 21 °C (−3320 kPa ± 3%) to 37 °C (−3195 kPa ± 5%) in agreement with the theoretical values, but was not statistically significant. Importantly, the effect of water treatment had a significant effect on the cavitation pressure for water with wetting agent (−3320 kPa ± 3%), degassed water (−1369 kPa ± 16%) and untreated distilled water (−528 kPa ± 25%). Thus, reducing dissolved gases through degassing or the use of a wetting agent significantly increases the cavitation pressure and reduces the variability of the cavitation pressure threshold

Perivascular network segmentations derived from high-field MRI and their implications for perivascular and parenchymal mass transport in the rat brain

Abstract A custom segmentation workflow was applied to ex vivo high-field MR images of rat brains acquired following in vivo intraventricular contrast agent infusion to generate maps of the perivascular spaces (PVS). The resulting perivascular network segmentations enabled analysis of perivascular connections to the ventricles, parenchymal solute clearance, and dispersive solute transport within PVS. Numerous perivascular connections between the brain surface and the ventricles suggest the ventricles integrate into a PVS-mediated clearance system and raise the possibility of cerebrospinal fluid (CSF) return from the subarachnoid space to the ventricles via PVS. Assuming rapid solute exchange between the PVS and CSF spaces primarily by advection, the extensive perivascular network decreased the mean clearance distance from parenchyma to the nearest CSF compartment resulting in an over 21-fold reduction in the estimated diffusive clearance time scale, irrespective of solute diffusivity. This corresponds to an estimated diffusive clearance time scale under 10 min for amyloid-beta which suggests that the widespread distribution of PVS may render diffusion an effective parenchymal clearance mechanism. Additional analysis of oscillatory solute dispersion within PVS indicates that advection rather than dispersion is likely the primary transport mechanism for dissolved compounds greater than 66 kDa in the long (> 2 mm) perivascular segments identified here, although dispersion may be significant for smaller compounds in shorter perivascular segments