Biology subjects

McFarland, K. N.

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

5 recordsLinked to original sources

bioRxiv2025

Progressive Supranuclear Palsy PERK haplotype B selectively translates DLX1 promoting tau toxicity

The unfolded protein response (UPR) sensor PERK exists in two haplotypes termed A and B. PERK-B uniquely confers increased risk for tauopathies like progressive supranuclear palsy (PSP), but the mechanisms distinguishing its function from PERK-A and contributing to its association with tau pathology are not known. Here, we developed a controlled cellular model for a pair-wise comparison of the two PERK haplotypes, finding their UPR functions nearly indistinguishable. However, a careful examination employing puromycin-based proteomics revealed that a subset of mRNA translation events were permissible under PERK-B, but not PERK-A, dependent UPR. Critically, one of the targets that escaped PERK-B suppression was the transcription factor DLX1, which has been genetically linked to PSP risk. Here, we found a shift in the solubility of DLX1 in human PSP brain tissue, and report that silencing of DLX-1 reduced the aggregation of tau in mammalian cells. Furthermore, silencing of the fly homolog of DLX1 was sufficient to decrease tau-induced toxicity, in vivo. Our results detail the haplotype-specific PERK-B/DLX-1 pathway as a novel driver of tau pathology in cells, flies, and likely human brain, revealing new insights into PSP pathogenesis and potential therapeutic targets.

neuroscience↗

bioRxiv2025

Differential age effects on functional network development link to contextual memory disruption in APOE4 versus APOE3 homozygous mice

Apolipoprotein-{varepsilon}4 (APOE4) homozygosity is the strongest genetic risk-factor for Alzheimers Disease (AD). The combined effects of APOE4 with age on the brain are unclear. In the present work, we tested the hypothesis that age alters contextual fear memory, functional network topology, diffusion imaging measures, and RNA expression differentially between APOE4 and APOE3 homozygous mice. Male and female mice, 1.5-5.5 month (young) and 9-13.5 month (adult), homozygous for human APOE4 or APOE3, were scanned using an 11.1 Tesla MRI scanner. Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) were performed, and images were processed and analyzed, followed by a contextual fear conditioning (CFC) protocol to test contextual memory. Functional imaging revealed decreases in various functional network measures and decreased network development for APOE4 adults as well as significant differences between groups in brain activity in motor, sensory, memory, and emotional processing related regions. APOE3 adult mice showed increasing network complexity with aging. DTI-based fractional anisotropy (FA) increased with age independent of genotype. Behaviorally APOE4 adult mice experienced contextual memory dysfunction relative to other groups. No sex differences were observed. The results suggest that in APOE4 adult mice there may be a link of network connectivity changes with increases in fear behavior and a decreased ability to recognize contextual changes. Furthermore, the lack of network development in aging APOE4 mice is indicative of a loss of functional network resilience in the brains of AD-susceptible individuals.

neuroscience↗

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↗