Biology subjects

Devine, A.

Publications and source records attributed to Devine, A..

4 recordsLinked to original sources

bioRxiv2026

Depth-Dependent Alterations in Cerebral Blood and Tissue Oxygenation Associated with Tau in Alzheimer's Disease Models

Vascular dysfunction is an increasingly recognized feature of Alzheimer's disease, and inadequate oxygen delivery may contribute to neuronal death. However, how cerebral oxygenation relates to neuronal pathology remains unclear. Here, we used two-photon phosphorescence lifetime microscopy with Oxyphor2P to measure intravascular and tissue partial pressure of oxygen (pO2) at 0, 100 and 200 um cortical depth in awake rTg4510 and THY-Tau22 mice. Relative to WT, capillary and venular pO2 in rTg4510 mice were elevated at 6 months but reduced at 9 months, mainly in deeper layers, with increased oxygen extraction fraction. Suppressing the tau transgene with doxycycline for three months did not restore vascular pO2. THY-Tau22 mice, despite limited tangle pathology, showed even greater reductions in capillary pO2 at every depth. In 6-month-old rTg4510 mice, tissue pO2 trended lower than in WT, and the fraction of low pO2 values (< 18 mmHg) increased with depth, reaching 33% at 200 um versus 4% in WT. Labeling neurofibrillary tangles with the tau-binding dye HS84 revealed significantly lower tissue pO2 in tangle-positive areas at 100 and 200 um. Longitudinal imaging of 2,282 neurons showed that disappearing neurons were not located in relatively hypoxic tissue within an animal. Finally, ex vivo immunostaining revealed neuronal loss and increased astrogliosis in rTg4510 mice, with unchanged vascular architecture. These results indicate that tau disrupts cerebrovascular and tissue oxygenation in a depth- and age-dependent manner, and that neuronal loss is not explained by a neuron's local oxygen microenvironment but may reflect a global reduction in cortical oxygenation.

neuroscience↗

bioRxiv2025

Tau drives cell specific functional isolation of the hippocampal formation

A major challenge in understanding Alzheimers disease is linking changes that occur across different biological scales. For example, how do changes in individual neurons build into widespread network disruptions? To address this, we used flexible mesh electronics to record neuronal activity for six months in ThyTau22 mice, a model of tauopathy that accumulates mutant human tau with age. Electrophysiology was recorded simultaneously from the hippocampus and entorhinal cortex of awake, behaving mice. At all ages we observed neuron-level, tau-driven silencing including ages without detectable tangles or cell-death. We found an unexpected phenomenon: neurons silenced by tau spontaneously recover individual firing patterns, yet these neurons fail to regain normal network interactions. Thus, as the animals age, disrupted network-level activity emerges. Specifically, we observe a global decrease in excitatory interactions and a breakdown in gamma-band coherence, which is particularly disrupted between the entorhinal cortex and hippocampus. These observations reveal a temporal relationship between neuronal silencing and impaired network connectivity, which also contributes to a progressive disruption in the excitatory/inhibitory balance. This ultimately disconnects viable entorhinal-hippocampal connections, physiologically isolating the hippocampus. Importantly, this network dysfunction is not driven by neuron loss, but by the failure of neurons to re-establish proper network interactions after silencing. This reveals a previously unrecognized mechanism by which mutant tau can destabilize neural systems. Further, these experiments indicate that a therapeutic window may exist where neuronal function and network activity might still be restored prior to irreversible degeneration.

neuroscience↗

bioRxiv2017

Tissue architectural cues drive the emergence of non-random trafficking of human tumor cells in the larval zebrafish

Sites of metastasis are non-random, with certain types of cancers showing organ preference during distal colonization. Using multiple brain- and bone marrow-seeking human and murine breast cancer subclones, we determined that tumor cells that home to specific murine organs (brain and bone marrow) ultimately colonized analogous tissues (brain and caudal vein plexus [CVP]) in larval zebrafish. We then exploited the zebrafish model to delineate factors leading to differential cell homing and extravasation. Bone marrow-tropic clones showed higher expression of integrins and focal adhesions associated with mechanosensing machinery than brain-tropic clones and were more sensitive to vessel topography during extravasation. Knockdown of {beta}1 integrin reduced extravasation and redistributed organ targeting from disordered vessels in the CVP to the brain. Our results show that organ selectivity is driven by topography- and cell type-dependent extravasation at the tumor-endothelial interface in the larval zebrafish and provide important insights into the early stages of metastasis.

biophysics↗

bioRxiv2017

Human macrophages survive and adopt activated genotypes in living zebrafish

The inflammatory response, modulated both by tissue resident macrophages and recruited monocytes from peripheral blood, plays a critical role in human diseases such as cancer and neurodegenerative disorders. Here, we sought a model to interrogate human immune behavior in vivo. We determined that primary human monocytes and macrophages survive in zebrafish for up to two weeks. Flow cytometry revealed that human monocytes cultured at the physiological temperature of the zebrafish survive and differentiate comparable to cohorts cultured at human physiological temperature. Moreover, key genes that encode for proteins that play a role in tissue remodeling were also expressed. Human cells migrated within multiple tissues at speeds comparable to zebrafish macrophages. Analysis of gene expression of in vivo educated human macrophages confirmed expression of activated macrophage phenotypes. Here, human cells adopted phenotypes relevant to cancer progression, suggesting that we can define the real time immune modulation of human tumor cells during the establishment of a metastatic lesion in zebrafish.

developmental biology↗