Tau Pathology Profile Across a Parietal-Hippocampal Brain Network Is Associated With Spatial Reorientation Learning and Memory Performance in the 3xTg-AD Mouse.

In early Alzheimer's disease (AD) spatial navigation is one of the first impairments to emerge; however, the precise cause of this impairment is unclear. Previously, we showed that, in a mouse model of tau and amyloid beta (Aß) aggregation, getting lost represents, at least in part, a failure to use distal cues to get oriented in space and that impaired parietal-hippocampal network level plasticity during sleep may underlie this spatial disorientation. However, the relationship between tau and amyloid beta aggregation in this brain network and impaired spatial orientation has not been assessed. Therefore, we used several approaches, including canonical correlation analysis and independent components analysis tools, to examine the relationship between pathology profile across the parietal-hippocampal brain network and spatial reorientation learning and memory performance. We found that consistent with the exclusive impairment in 3xTg-AD 6-month female mice, only 6-month female mice had an ICA identified pattern of tau pathology across the parietal-hippocampal network that were positively correlated with behavior. Specifically, a higher density of pTau positive cells predicted worse spatial learning and memory. Surprisingly, despite a lack of impairment relative to controls, 3-month female, as well as 6- and 12- month male mice all had patterns of tau pathology across the parietal-hippocampal brain network that are predictive of spatial learning and memory performance. However, the direction of the effect was opposite, a negative correlation, meaning that a higher density of pTau positive cells predicted better performance. Finally, there were not significant group or region differences in M78 density at any of the ages examined and ICA analyses were not able to identify any patterns of 6E10 staining across brain regions that were significant predictors of behavioral performance. Thus, the pattern of pTau staining across the parietal-hippocampal network is a strong predictor of spatial learning and memory performance, even for mice with low levels of tau accumulation and intact spatial re-orientation learning and memory. This suggests that AD may cause spatial disorientation as a result of early tau accumulation in the parietal-hippocampal network.

Mesenchymal stem cell-derived extracellular vesicles ameliorate Alzheimer's disease-like phenotypes in a preclinical mouse model.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that affects more than 44 million people worldwide. Despite the high disease burden, there is no effective treatment for people suffering from AD. Mesenchymal stem cells (MSCs) are multipotent stromal cells that have been widely studied due to their therapeutic potential. However, administration of cells has been found to have a multitude of limitations. Recently, extracellular vesicles (EVs) derived from MSCs have been studied as a therapeutic candidate, as they exhibit similar immunoprotective and immunomodulatory abilities as the host human MSCs. Methods: To test the potential therapeutic effects of MSC EVs, human bone-marrow derived MSCs were grown in three-dimensional (3D) cell culture, and small EVs were harvested using differential ultracentrifugation. These small EVs were given to non-transgenic (NT) or 5XFAD (5 familial Alzheimer's disease mutations) mice intranasally (IN) every 4 days for 4 months. The mice were then required to perform a variety of behavioral assays to measure changes in learning and memory. Afterwards, immunohistochemistry was performed on brain slices to measure amyloid beta (Aß) and glial fibrillary acidic protein (GFAP) levels. Results: The data revealed that 5XFAD mice that received hMSC-EV treatment behaved significantly better in cognitive tests than saline treated 5XFAD mice, with no significant change between EV-treated 5XFAD mice and NT mice. Additionally, we found lower Aß plaque load in the hippocampus of the EV-treated mice. Finally, less colocalization between GFAP and Aß plaques was found in the brain of EV-treated mice compared to saline. Conclusions: Taken together, these data suggest that IN administration of MSC-derived EVs can slow down AD pathogenesis.

Impaired Hippocampal-Cortical Interactions during Sleep in a Mouse Model of Alzheimer's Disease.

Spatial learning is impaired in humans with preclinical Alzheimer's disease (AD). We reported similar impairments in 3xTg-AD mice learning a spatial reorientation task. Memory reactivation during sleep is critical for learning-related plasticity, and memory consolidation is correlated with hippocampal sharp wave ripple (SWR) density, cortical delta waves (DWs), cortical spindles, and the temporal coupling of these events-postulated as physiological substrates for memory consolidation. Further, hippocampal-cortical discoordination is prevalent in individuals with AD. Thus, we hypothesized that impaired memory consolidation mechanisms in hippocampal-cortical networks could account for spatial memory deficits. We assessed sleep architecture, SWR-DW dynamics, and memory reactivation in a mouse model of tauopathy and amyloidosis implanted with a recording array targeting isocortex and hippocampus. Mice underwent daily recording sessions of rest-task-rest while learning the spatial reorientation task. We assessed memory reactivation by matching activity patterns from the approach to the unmarked reward zone to patterns during slow-wave sleep (SWS). AD mice had more SWS, but reduced SWR density. The increased SWS compensated for reduced SWR density so there was no reduction in SWR number. In control mice, spindles were phase-coupled with DWs, and hippocampal SWR-cortical DW coupling was strengthened in post-task sleep and was correlated with performance on the spatial reorientation task the following day. However, in AD mice, SWR-DW and spindle-DW coupling were impaired. Thus, reduced SWR-DW coupling may cause impaired learning in AD, and spindle-DW coupling during short rest-task-rest sessions may serve as a biomarker for early AD-related changes in these brain dynamics.

Impaired Spatial Reorientation in the 3xTg-AD Mouse Model of Alzheimer's Disease.

In early Alzheimer's disease (AD) spatial navigation is impaired; however, the precise cause of this impairment is unclear. Recent evidence suggests that getting lost is one of the first impairments to emerge in AD. It is possible that getting lost represents a failure to use distal cues to get oriented in space. Therefore, we set out to look for impaired use of distal cues for spatial orientation in a mouse model of amyloidosis (3xTg-AD). To do this, we trained mice to shuttle to the end of a track and back to an enclosed start box to receive a water reward. Then, mice were trained to stop in an unmarked reward zone to receive a brain stimulation reward. The time required to remain in the zone for a reward was increased across training, and the track was positioned in a random start location for each trial. We found that 6-month female, but not 3-month female, 6-month male, or 12-month male, 3xTg-AD mice were impaired. 6-month male and female mice had only intracellular pathology and male mice had less pathology, particularly in the dorsal hippocampus. Thus, AD may cause spatial disorientation as a result of impaired use of landmarks.