Biology subjects

McFarland, K. N.

Publications and source records attributed to McFarland, K. N..

3 recordsLinked to original sources

bioRxiv2024

Sex dependent effects of amyloidosis on functional network hub topology is associated with downregulated neuronal gene signatures in the APPswe/PSEN1dE9 double transgenic mouse

BackgroundExtracellular amyloid-{beta} (A{beta}) impairs brain-wide functional connectivity, although mechanisms linking A{beta} to broader functional network connectivity remain elusive. ObjectiveHere, we evaluated the effect of A{beta} on fear memory and functional connectome measures in mice. MethodsMiddle-aged (9-11 months of age) double transgenic APP-PS1 mice and age and sex-matched controls were evaluated on a fear conditioning protocol and then imaged at 11.1 Tesla. Brains were harvested and processed for analysis of A{beta} plaques and Iba1 immunolabeling in cortex, hippocampus, and basolateral amygdala. Additional RNA sequencing data from separate age, strain, and sex matched mice were analyzed for differentially expressed genes (DEGs) and weighted gene co-expression networks. ResultsIn both male and female mice, we observed increased functional connectivity in a dorsal striatal/amygdala network due to A{beta}. Increased functional connectivity within this network was matched by increases in A{beta}PP gene expression, A{beta} and Iba1 immunolabeling, and an upregulated cluster of DEGs involved in the immune response. Conversely, the network measure representing node hubness, eigenvector centrality, was increased in prefrontal cortical brain regions, but only in female APP-PS1 mice. This female specific-effect of amyloid was associated with downregulation of a cluster of DEGs involved in cortical and striatal GABA transmission, anxiogenic responses, and motor activity, in female APP-PS1 mice, but not males. ConclusionsOur results contribute to a growing literature linking between A{beta}, immune activation and functional network connectivity. Furthermore, they reveal effects of A{beta} on gene expression patterns in female mice that may contribute to amyloidosis-induced dysregulation of non-cognitive circuitry.

neuroscience↗

bioRxiv2024

Human APOE allelic variants suppress the formation of diffuse and fibrillar Aβ deposits relative to mouse Apoe in transgenic mouse models of Alzheimer amyloidosis

BackgroundApolipoprotein E (apoE) modulates the deposition of amyloid {beta} (A{beta}) aggregates in Alzheimers disease (AD) in an isoform-dependent manner. In transgenic mouse models of AD-amyloidosis, replacing mouse Apoe alleles with human APOE variants suppresses fibrillar A{beta} deposits. In the PD-APP transgenic mouse model, deletion of the Apoe gene led to selective reduction of fibrillar deposits with increased diffuse deposits. This finding suggested that apoE may have differential effects on different types of amyloid pathology. MethodsHere, we investigated the interaction between the type of A{beta} pathology in the brain and human apoE isoforms in different transgenic mouse models. ResultsIn the APPsi model that develops predominantly diffuse A{beta} plaques late in life, we determined that replacing mouse Apoe with human APOE3 or APOE4 genes potently suppressed diffuse amyloid formation, with apoE3 exhibiting a greater activity relative to apoE4. Relative to apoE4, apoE3 appeared to suppress A{beta} deposition in the cerebral vasculature. In a second cohort, we accelerated the deposition of diffuse A{beta} pathology by seeding, finding that seeded APPsi mice harboring APOE4 or APOE3 developed equal burdens of diffuse parenchymal A{beta}. Finally, in the recently developed SAA-APP model that has a mix of dense-core and fibrous A{beta} plaques, we found that replacing mouse apoE with human apoE suppressed deposition significantly, with the amyloid burden following the trend of Apoe>>APOE4> APOE3[~]APOE2. In the SAA-APP and seeded APPsi models, we found evidence of apoE protein associated with A{beta} plaques. ConclusionsOverall, these observations demonstrate a capacity for human apoE to suppress the deposition of both diffuse and fibrillar-cored deposits, relative to mouse apoE. Notably, in the seeded paradigm, the suppressive activity of human apoE3 and apoE4 appeared to be overwhelmed. Taken together, this study demonstrates that APOE genotype influences the deposition of both cored-fibrillar and diffuse amyloid.

neuroscience↗

bioRxiv2021

Microglia show differential transcriptomic response to Aβ peptide aggregates ex vivo and in vivo

Aggregation and accumulation of amyloid-{beta} (A{beta}) is a defining feature of Alzheimers disease (AD) pathology. To study microglial responses to A{beta}, we applied exogenous A{beta} peptide, in either oligomeric or fibrillar conformation, to primary mouse microglial cultures and evaluated system level transcriptional changes and then compared these to transcriptomic changes in the brains of CRND8 APP mice. We find that primary microglial cultures have rapid and massive transcriptional change to in response to A{beta}. Transcriptomic responses to oligomeric or fibrillar A{beta} in primary microglia, though partially overlapping, are distinct and are not recapitulated in vivo where A{beta} progressively accumulates. Furthermore, though classic immune mediators show massive transcriptional changes in the primary microglial cultures, these changes are not observed in the mouse model. Together, these data extend previous studies which demonstrate that microglia responses ex vivo are poor proxies for in vivo responses. Finally, these data demonstrate the potential utility of using microglia as biosensors of different aggregate conformation, as the transcriptional responses to oligomeric and fibrillar A{beta} can be distinguished.

neuroscience↗