Biology subjects

Collins-Praino, L. E.

Publications and source records attributed to Collins-Praino, L. E..

5 recordsLinked to original sources

bioRxiv2026

Engineering a Novel Bacterial Encapsulin for Programmable Surface Functionalization: From Single-Target to Mosaic Nanovaccines

Encapsulins are prokaryotic self-assembling protein nanocages with promise as nanovaccine scaffolds. Their utility as modular platforms require tolerance to surface engineering, high-yield soluble production, formulation stability, and controlled antigen (co-)display. Herein, a previously uncharacterized encapsulin from Alkaliphilus metalliredigens is engineered into a SpyCatcher-decorated nanoscaffold (Am-S) that enables controlled surface display of SpyTagged antigens. Cryo-EM confirms that the native encapsulin forms a T = 1 icosahedral nanocage, and that C-terminal SpyCatcher fusion yields Am-S without compromising nanocage assembly, symmetry, or structural integrity. Notably, Am-S exhibits high-yield soluble production in Escherichia coli, remains monodisperse after freeze-thaw and extended storage, and supports efficient SpyTagged peptide conjugation for single- and multi-antigen display. As a proof-of-concept, Am-S is functionalized with Alzheimers disease-associated amyloid-{beta} and/or hyperphosphorylated tau epitopes to generate single-target nanocages displaying either antigen and dual-target mosaic nanocages co-displaying both. In mice, Am-S antigen display enhances antigen-specific IgG responses relative to free antigens and induces predominantly IgG1-biased humoral immunity. Mosaic nanocages elicit antibodies against both targets, with immune sera selectively recognizing amyloid-{beta}- and phosphorylated tau-associated pathology in ex vivo brain sections from Alzheimers disease mouse models. These findings position Am-S as a manufacturable scaffold for developing multi-targeting nanovaccines against complex diseases.

synthetic biology↗

bioRxiv2024

Protein Coronas Derived from Cerebrospinal Fluid Enhance the Interactions Between Nanoparticles and Brain Cells

Neuronanomedicine harnesses nanoparticle technology for the treatment of neurological disorders. An unavoidable consequence of nanoparticle delivery to biological systems is the formation of a protein corona on the nanoparticle surface. Despite the well-established influence of the protein corona on nanoparticle behavior and fate, as well as FDA approval of neuro-targeted nanotherapeutics, the effect of a physiologically relevant protein corona on nanoparticle-brain cell interactions is insufficiently explored. Indeed, less than 1% of protein corona studies have investigated protein coronas formed in cerebrospinal fluid (CSF), the fluid surrounding the brain. Herein, we utilize two clinically relevant polymeric nanoparticles (PLGA and PLGA-PEG) to evaluate the formation of serum and CSF protein coronas. LC-MS analysis revealed distinct protein compositions, with selective enrichment/depletion profiles. Following incubation with brain cells, serum and CSF coronas on PLGA particles showed enhanced associations with all cell types as compared to their corresponding corona on PLGA-PEG particles. CSF-derived protein coronas on PLGA nanoparticles, specifically, showed the greatest nanoparticle-cell interactions, with Pearsons correlation analysis revealing that proteins associated with enhanced nanoparticle-cell interactions were exclusively enriched in this protein corona. This study demonstrates the importance of correct choice of physiologically relevant biological fluids, and its influence on the formation of the protein corona, subsequent nanoparticle-cell interactions.

bioengineering↗

bioRxiv2024

Changes in cognition and neuroinflammation in a rodent model of chemotherapy-induced cognitive impairment are variable both acutely and chronically

Chemotherapy-induced cognitive impairment (CICI) affects up to 75% of cancer survivors between 6-months and 20-years post-treatment. Impairments include memory loss, learning difficulties, inability to concentrate and a decrease in processing speed, all of which can negatively impact quality of life. Several mechanisms are proposed to drive these impairments, with evidence implicating neuroinflammation as a key contributor. However, the time course over which impairments occur is less well-established. Several preclinical studies have focused on acute (0-7 days) and sub-acute (8-days to 12-weeks) time-points following chemotherapy, but few have investigated more longer-term time-points. This study therefore aimed to understand the evolution of cognitive changes following methotrexate (MTX) or 5-flurouracil (5-FU) chemotherapy treatment, assessing three time-points: acute (96-hour), sub-acute (31-days) and chronic (93-days). Further, we investigated whether alterations in cognition were associated with concomitant changes in neuroinflammation, assessed via astrocytic reactivity. Female Sprague Dawley rats received two intraperitoneal injections of MTX, 5-FU or saline and were assessed on the novel object recognition, 5-choice serial reaction time task and Barnes maze. Hippocampal (HIPP) and pre-frontal cortex (PFC) tissue was examined for GFAP expression. Results indicate that both MTX and 5-FU exposure were associated with impairments in spatial memory, task acquisition, and processing speed at 31-days, with impairment ameliorated by 93-days post-treatment. While MTX and 5-FU increased GFAP expression across all time-points, with the largest changes at 96-hours and 31-days, drug-specific and region-specific variations were noted. These results provide valuable insight into the complexity of the neuroinflammatory response in CICI. While neuroinflammation may be a promising therapeutic target, further work is required to fully understand this response, including which aspects to target and at what time-points, to ensure optimal outcomes for cancer patients treated with chemotherapy.

animal behavior and cognition↗

bioRxiv2023

Leakage beyond the primary infarction: A temporal analysis of cerebrovascular dysregulation at sites of hippocampal secondary neurodegeneration following cortical photothrombotic stroke

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-{beta} accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-{beta} around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the colocalization of amyloid-{beta} with vasculature and blood-brain-barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that was exacerbated in vessels with amyloid-{beta} deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood-brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.

neuroscience↗

bioRxiv2021

Fyn kinase inhibition using AZD0530 improves recognition memory and reduces depressive-like behaviour in an experimental model of Parkinson's disease

Fyn kinase has recently been established as a major upstream regulator of neuroinflammation in PD. This study aimed to determine if inhibition of Fyn kinase could lead to reduced neuroinflammation and improvements in motor and non-motor impairments in an early-stage model of PD. An experimental model of PD was produced using intra-striatal injection (4{micro}l) of the neurotoxin 6-OHDA (5{micro}g/{micro}l). Sprague Dawley rats (n=42) were given either vehicle, 6mg/kg or 12mg/kg of Fyn kinase inhibitor (AZD0530) daily for 32 days via oral gavage and tested on a battery of tasks assessing motor, cognitive and neuropsychiatric outcomes. AZD 0530 administration led to improvement in volitional locomotion and recognition memory, as well as a reduction in depressive-like behaviour. Pathologically, an inflammatory response was observed; however, there were no significant differences in markers of neuroinflammation between treatment groups. Taken together, results indicate a potential therapeutic benefit for use of Fyn kinase inhibition to treat non-motor symptoms of PD, although mechanisms remain to be elucidated. HIGHLIGHTSO_LIFyn kinase has recently been proposed as a major upstream regulator of microglial activation in Parkinsons disease (PD). C_LIO_LIThis study was the first to evaluate the effects of Fyn kinase inhibition in a rodent model of PD. C_LIO_LIFyn kinase inhibition using the Fyn kinase inhibitor AZD 0530 was capable of improving volitional locomotion and recognition memory and reducing depressive-like behaviour in a rodent model of PD. C_LIO_LIInterestingly, while increases in microglial activation were observed in this rodent model of PD, AZD 0530 did not significantly reduce this activation. C_LIO_LIThis suggests that the behavioural improvements associated with Fyn kinase inhibition may occur independently of neuroinflammation and may be attributable to other brain mechanisms, including actions on NMDA or 5-HT6 receptors. C_LI

neuroscience↗