Biology subjects

Alyenbaawi, H.

Publications and source records attributed to Alyenbaawi, H..

3 recordsLinked to original sources

bioRxiv2026

Seizures and tauopathy following neurotrauma are mediated by prion protein and metabotropic glutamate receptor 5

Traumatic brain injury (TBI) is one of the world's leading causes of death and disability and a major risk factor for dementias. The primary dementia associated with TBI is chronic traumatic encephalopathy (CTE), a neurodegenerative disease classified as a tauopathy, in which toxic tau molecules lead to disease pathologies and degeneration. The processes that lead to tauopathy and subsequent dementia after TBI remain unclear. Here, we built upon the finding that seizures after TBI may be a mechanism leading to tauopathy, by dissecting the functions of the metabotropic glutamate receptor 5 - cellular prion protein (mGluR5-PrPC) pathway. We delivered TBI to larval in a blast paradigm, and quantified aggregation of Tau via a genetically-encoded Tau-GFP fusion reporter. Zebrafish larvae lacking prp2 (homolog of mammalian cellular Prion Protein, PrPC) displayed a 168% increase in post-traumatic seizures activity after TBI. An mGluR5 agonist (CHPG) reduced post-traumatic seizures, whereas an mGluR5 antagonist (MPEP) increased post-traumatic seizures. Moreover, agonizing mGluR5 reduced tau aggregation and antagonizing mGluR5 increased tau burden. Larvae seizing from convulsants, rather than TBI, were treated with CHPG/MPEP and provided a similar pattern of outcomes, suggesting seizures may be a factor needed for mGluR5 activity to influence tau aggregation. The PrPC-mGluR5 pathway is proposed as one candidate pathomechanism linking TBI to subsequent seizures and tauopathy, and thus it warrants investigation as a target for prophylactic interventions.

neuroscience↗

bioRxiv2024

A larval zebrafish model of TBI: Optimizing the dose of neurotrauma for discovery of treatments and aetiology

Traumatic brain injuries (TBI) are diverse with heterogeneous injury pathologies, which creates challenges for the clinical treatment and prevention of secondary pathologies such as post-traumatic epilepsy and subsequent dementias. To develop pharmacological strategies that treat TBI and prevent complications, animal models must capture the spectrum of TBI severity to better understand pathophysiological events that occur during and after injury. To address such issues, we improved upon our recent larval zebrafish TBI paradigm emphasizing titrating to different injury levels. We observed coordination between an increase in injury level and clinically relevant injury phenotypes including post-traumatic seizures (PTS) and tau aggregation. This preclinical TBI model is simple to implement, allows dosing of injury levels to model diverse pathologies, and can be scaled to medium- or high-throughput screening.

neuroscience↗

bioRxiv2020

Seizures are a druggable mechanistic link between TBI and subsequent tauopathy

Traumatic brain injury (TBI) is a prominent risk factor for neurodegenerative diseases and dementias including chronic traumatic encephalopathy (CTE). TBI and CTE, like all tauopathies, are characterized by accumulation of Tau into aggregates that progressively spread to other brain regions in a prion-like manner. The mechanisms that promote spreading and cellular uptake of tau seeds after TBI are not fully understood, in part due to lack of tractable animal models. Here, we test the putative roles for excess neuronal activity and dynamin-dependent endocytosis in promoting the in vivo spread of tauopathy. We introduce tauopathy reporter zebrafish expressing a genetically-encoded fluorescent Tau biosensor that reliably reports accumulation of human tau species when seeded via intra-ventricular brain injections. Subjecting zebrafish larvae to a novel TBI paradigm produced various TBI symptoms including cell death, hemorrhage, blood flow abnormalities, post-traumatic seizures, and Tau inclusions. Bath application of anticonvulsant drugs rescued TBI-induced tauopathy and cell death; these benefits were attributable to inhibition of post-traumatic seizures because co-application of convulsants reversed these beneficial effects. However, one convulsant drug, 4-Aminopyridine, unexpectedly abrogated TBI-induced tauopathy - this was due to its inhibitory action on endocytosis as confirmed via additional dynamin inhibitors. These data suggest a role for seizure activity and dynamin-dependent endocytosis in the prion-like seeding and spreading of tauopathy following TBI. Further work is warranted regarding anti-convulsants that dampen post-traumatic seizures as a route to moderating subsequent tauopathy. Moreover, the data highlight the utility of deploying in vivo Tau biosensor and TBI methods in larval zebrafish, especially regarding drug screening and intervention. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/091819v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@34a2caorg.highwire.dtl.DTLVardef@1ab916borg.highwire.dtl.DTLVardef@d83bf2org.highwire.dtl.DTLVardef@47bf90_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIntroduces first Traumatic Brain Injury (TBI) model in larval zebrafish, and its easy C_LIO_LITBI induces clinically relevant cell death, haemorrhage & post-traumatic seizures C_LIO_LICa2+ imaging during TBI reveals spike in brain activity concomitant with seizures C_LIO_LITau-GFP Biosensor allows repeated in vivo measures of prion-like tau aggregation C_LIO_LIpost-TBI, anticonvulsants stop tauopathies akin to Chronic Traumatic Encephalopathy C_LI

neuroscience↗