Atrophy associated with tau pathology precedes overt cell death in a mouse model of progressive tauopathy.

Tau pathology in Alzheimer's disease (AD) first develops in the entorhinal cortex (EC), then spreads to the hippocampus, followed by the neocortex. Overall, tau pathology correlates well with neurodegeneration and cell loss, but the spatial and temporal association between tau pathology and overt volume loss (atrophy) associated with structural changes or cell loss is unclear. Using in vivo magnetic resonance imaging (MRI) with tensor-based morphometry (TBM), we mapped the spatiotemporal pattern of structural changes in a mouse model of AD-like progressive tauopathy. A novel, coregistered in vivo MRI atlas was then applied to identify regions in the medial temporal lobe that had a significant volume reduction. Our study shows that in a mouse model of tauopathy spread, the propagation of tau pathology from the EC to the hippocampus is associated with TBM-related atrophy, but atrophy in the dentate gyrus and subiculum precedes overt cell loss.

Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology.

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.

Direct brain infusion can be enhanced with focused ultrasound and microbubbles.

The delivery of most therapeutic agents is rendered ineffective for the treatment of brain diseases due to the presence of the blood-brain barrier (BBB). The goal of this study was to investigate the effect of pre-infusion focused ultrasound (FUS) and microbubbles on the distribution of direct brain infusion in vivo. A single-element FUS transducer was used in all sonications, which were carried out immediately prior to direct infusion procedures. Mice received direct infusion of either Gadolinium-labeled albumin (Gd-albumin, 74 kDa) or adeno-associated virus (AAV, ∼4 MDa). The volumes of Gd-albumin at 30 min were deemed comparable ( P = 0.334) between the direct infusion (DI)-only group and the FUS + DI group. At 120 min, the FUS + DI group showed significantly higher contrast-enhanced volume (9.76 ± 0.74 mm3) than the DI-only group (7.14 ± 0.34 mm3). For mice infused with AAV, the total volume of transduction was estimated as GFP-positive regions and FUS + DI group demonstrated significantly higher ( P = 0.017) transduction efficiency in vivo. In conclusion, enhanced bio-distribution of directly infused agents was observed when the targeted region was pre-conditioned with FUS and microbubbles. Focused ultrasound has the potential, as an adjuvant technique, to significantly enhance direct brain infusion and achieve the desired therapeutic outcomes.

Real-time rolling circle amplification for protein detection.

Real-time nucleic acid amplification methods can be extremely useful for the identification and quantitation of nucleic acid analytes, but are more difficult to adapt to protein or other analytes. To facilitate the development of real-time rolling circle amplification (RCA) for protein targets, we have developed a novel type of conformation-switching aptamer that can be circularized upon interaction with its protein target, the platelet-derived growth factor (PDGF). Using the structure-switching aptamer, real-time RCA can be used to specifically quantitate PDGF down to the low-nanomolar range (limit of detection, 0.4 nM), even against a background of cellular lysate. The aptamer can also be adapted to RCA on surfaces, although quantitation proved to be more difficult. One of the great advantages of the method described herein is that it can be immediately adapted to almost any aptamer and does not require two or more affinity reagents as do sandwich or proximity assays.