Biology subjects

Brady, E.

Publications and source records attributed to Brady, E..

5 recordsLinked to original sources

bioRxiv2026

Therapeutic targeting of fibrin-microglia interactions ameliorates Alzheimer disease-related hyperexcitability and brain network dysfunction

Brain network dysfunction--including hyperexcitability, altered oscillations, and sleep disruption--is prominent in Alzheimers disease (AD), but the contribution of vascular-neuroimmune processes to these alterations remains unclear. Here, we blocked the pro-inflammatory interaction of the blood protein fibrin with microglia using genetic (Fgg{gamma}390-396A mice) and antibody-based (5B8 and THN392) strategies to test its role in AD-related network dysfunction. The 5xFAD model of AD exhibited network hyperexcitability associated with oscillatory slowing, sleep states, and disrupted sleep-circadian rhythms. These deficits were largely attenuated by blocking fibrin-microglia interactions in 5xFAD;Fgg{gamma}390-396A mice. Notably, pharmacological interventions after disease onset with both anti-fibrin antibodies similarly attenuated these AD-related network deficits and behavioral abnormalities. We conclude that vascular-neuroimmune processes driven by fibrin-microglia interactions promote AD-related network dysfunction and that targeting the fibrin-microglia axis--currently under clinical evaluation with the humanized antibody THN391-- represents a promising therapeutic strategy for AD. There is a companion manuscript submitted to bioRxiv (Yan et al., 2026).110 HIGHLIGHTSO_LIFibrin promotes AD-related network hyperexcitability and oscillatory slowing in 5xFAD mice C_LIO_LIFibrin promotes AD-related disruption of sleep and circadian rhythms in 5xFAD mice C_LIO_LIGenetic blocking of fibrin-microglia interactions rescues AD-related brain network dysfunction C_LIO_LIAnti-fibrin antibodies (5B8 and THN392) show acute and chronic therapeutic benefit C_LI

neuroscience↗

bioRxiv2025

APOE4-Aβ synergy drives brain network dysfunction and neuronal lysosomal-ER proteostasis dysregulation in preclinical Alzheimer's disease

Amyloid-{beta} (A{beta}) and APOE4 represent two of the strongest pathological and genetic risk factors for Alzheimers disease (AD), but how these co-pathogens interact during preclinical stages remains undefined. We addressed this question by developing a humanized knock-in model expressing physiological, endogenously regulated human A{beta} and APOE4. Aged AppNLF:APOE4 mice displayed incipient amyloidosis with subtle memory-related changes, consistent with preclinical AD. We found largely distinct, non-overlapping APOE4- and A{beta}-driven functional synaptic, sleep, and behavioral alterations. However, at the transcriptomic level, APOE4xA{beta} had a pronounced detrimental interaction in neuronal populations, whereas glial populations were primarily affected by either genotype. We found APOE4xA{beta} molecular interactions in neuronal populations, including excitatory and inhibitory cells, converged on a core lysosomal-ER proteostasis axis. We propose that APOE4xA{beta} interaction produces an early neuronal pathogenic signature, involving the lysosomal-ER proteostasis axis, preceding functional decline and driving disease progression. APOE4xA{beta}-KI models provide a physiologically relevant platform to study early pathogenesis. HighlightsO_LIEarly synergistic APOE4xA{beta} interaction emerges predominantly at the transcriptomic level in neurons, but not in glial cells. C_LIO_LIAPOE4 and A{beta} drive largely non-overlapping physiological changes in preclinical stages of disease, but converge at the level of network hyperexcitability. C_LIO_LIAPOE4xA{beta} neuronal synergy converges on a conserved lysosomal-ER proteostasis axis. C_LIO_LIHumanized APOE4xA{beta} KI mice provide a physiologically relevant model to dissect early AD pathogenesis in preclinical stages C_LI

neuroscience↗

bioRxiv2023

Long chain monomethyl branched-chain fatty acid levels in human milk vary with gestational weight gain

Breastfeeding is an important determinant of infant health and there is immense interest in understanding its metabolite composition so that key beneficial components can be identified. The aim of this research was to measure the fatty acid composition of human milk in an Irish cohort where we examined changes depending on lactation stage and gestational weight gain trajectory. Utilising a chromatography approach optimal for isomer separation, we identified 44 individual fatty acid species via GCMS and showed that monomethyl branched-chain fatty acids(mmBCFAs), C15:0 and C16:1 are lower in women with excess gestational weight gain versus low gestational weight gain. To further explore the potential contribution of the activity of endogenous metabolic pathways to levels of these fatty acids in milk, we administered D2O to C57BL/6J dams fed a purified lard based high fat diet (HFD) or low-fat diet during gestation and quantified the total and de novo synthesized levels of fatty acids in their milk. We found that de novo synthesis over three days can account for between 10 and 50% of mmBCFAs in milk from dams on the low-fat diet dependent on the branched-chain fatty acid species. However, HFD fed mice had significantly decreased de novo synthesized fatty acids in milk resulting in lower total mmBCFAs and medium chain fatty acid levels. Overall, our findings highlight the diverse fatty acid composition of human milk and that human milk mmBCFA levels differ between gestational weight gain phenotypes. In addition, our data indicates that de novo synthesis contributes to mmBCFA levels in mice milk and thus may also be a contributory factor to mmBCFA levels in human milk. Given emerging data indicating mmBCFAs may be beneficial components of milk, this study contributes to our knowledge around the phenotypic factors that may impact their levels.

physiology↗

bioRxiv2021

Chemogenetic activation of midline thalamic nuclei fails to ameliorate memory deficits in two mouse models of Alzheimer's disease

One of the main features of Alzheimers disease is the progressive loss of memory, likely due to pathological changes within brain regions such as the hippocampus and entorhinal cortex. These structures are embedded within the extended memory circuit, an interconnected set of brain regions that are essential for episodic memory. The anterior thalamic nuclei (ATN) and thalamic nucleus reuniens (NRe) are both extensively and reciprocally connected with these important memory regions, so we sought to test the hypothesis that chemogenetically-enhancing neurotransmission through NRe and ATN would ameliorate memory deficits in two mechanistically-distinct mouse models of Alzheimers disease. Using the hAPP-J20 mouse model of amyloidopathy and the Tg4510 mouse model of tauopathy, we carried out stereotaxic injections of viral vectors to transduce hM3Dq (Gq)_mCherry into NRe or the anterio-dorsal/anterio-ventral nuclei of ATN, using mCherry as a control. At nine months (hAPP-J20) or six months (Tg4510) of age, mice underwent a behaviour battery of open field (OF), novel object recognition (NOR) and radial arm maze (RAM), with DREADD agonist 21 administered 30min prior to each behaviour test. Tissue was collected post-behaviour to confirm injection site and virus expression. Both Tg4510 and hAPP-J20 mice show marked hyperactivity in the OF, significant deficits in recognition memory, and a significant impairment in spatial reference and spatial working memory. Unexpectedly, chemogenetic activation of ATN or NRe did not significantly improve spatial memory impairments or reduce the observed hyperactivity, although NRe activation did modestly rescue recognition memory in J20 mice. This may be due to compensation elsewhere within the memory circuit, or that the pathological changes are too far advanced for behaviour reversal.

neuroscience↗

bioRxiv2020

Design, construction, and advantages of 100% online laboratories in an upper division undergraduate biology course

For centuries, students have been taught by passively listening to lectures, usually in large groups. In many fields, this type of course delivery is not ideal. In addition, students that have grown up with online access and/or have been forced to take online course during the recent pandemic, are seeking improved online educational experiences. As providers of education, Universities must adapt to this rapidly changing environment. The emergence of exciting, "disruptive" technologies has provided the tools needed for educators to revolutionize the delivery of higher education. The University of Florida, through UF Online, provides students the opportunity to enroll in fully online four-year undergraduate degrees. In this report, we describe the development of fully online laboratories for the upper-division course Evolutionary Developmental Biology, which fulfill the University of Floridas laboratory requirement. This course is taken by Biology, Zoology, and related majors, including majors in the 100% online Biology degree. The experiments in the virtual laboratories would have been impossible to teach in a residential setting due to time constraints, cost, student safety issues, and regulatory/certification requirements. The ability to perform these experiments online provided University of Florida undergraduates located throughout the world access to unique, one-of-a-kind laboratory experiences. The virtual laboratories allowed students to undertake in-depth exploration and application of course content that is not possible in a residential setting. Completion of the Evolutionary Developmental Biology course provided undergraduate students the opportunity to obtain a science degree without ever visiting the universitys residential campus. During the Fall 2020 term, this course was made available to residential students, thus allowing this cohort of students to continue to make progress, 100% online, towards their undergraduate degree during the COVID19 pandemic.

developmental biology↗