Biology subjects

Bastlund, J. F.

Publications and source records attributed to Bastlund, J. F..

4 recordsLinked to original sources

bioRxiv2026

5-MOP: a novel and selective colony stimulating factor-1 receptor (CSF1R) radiotracer

Colony stimulating factor 1 receptor (CSF1R) is a tyrosine kinase receptor that is expressed exclusively in microglia within the CNS. Its endogenous ligands, colony stimulating factor-1 (CSF1) and interleukin-34 (IL-34), are released from neurons, positioning CSF1R as a key mediator receptor of neuron-glia communication. CSF1R is considered not only a potential drug target, but also a biomarker of neuroinflammation. From that perspective, selective radioligands for neuroimaging are of great interest for imaging neuroinflammation and determining drug occupancy. In this study, we have validated the binding characteristics of a CSF1R inhibitor, 4-((5-MethOxy-6-((5-methoxypyridin-2-yl)methoxy)pyridin-3-yl)methyl)-2-(1-methyl-1H-pyrazol-4-yl)pyrimidine (5-MOP) as a novel CSF1R radioligand, by performing in vitro saturation binding experiments in human and murine tissues. 5-MOP was found to be selective for CSF1R among a broad range of kinases. Autoradiography revealed that [3H]5-MOP binds with high affinity (KD = 9.8 nM) to a single saturable binding site in human meningioma tissues, and this binding was displaced with known CSF1R inhibitors, including CPPC, sCSF1inh and GW-2580. In contrast, CPPC, which has been extensively used as a CSF1R radioligand showed substantial cross-reactivity to other brain kinases, including Trk A/B/C, and [3H]CPPC could only be displaced with CPPC itself, not by other ligands, including 5-MOP. These results identify [3H]5-MOP as the most selective radioligand currently available, enabling accurate detection of drug occupancy and activated microglia. Significance of the studyThis study identifies and validates a novel selective radioligand that binds CSF1R with high selectivity and low nanomolar affinity. Because CSF1R is selectively expressed in activated microglia, this radioligand could be useful for detecting neuroinflammatory activity.

neuroscience↗

bioRxiv2025

T-401 binding to monoacylglycerol lipase (MAGL) in the brains of patients and mice with temporal lobe epilepsy

Monoacylglycerol lipase (MAGL) inhibitors are considered as drug candidates for epilepsy. In order to determine the level of MAGL and evaluate changes in the epileptic brain, we have validated and used autoradiography and the MAGL radiotracer [3H]T-401 on resected temporal neocortex specimens obtained from patients with temporal lobe epilepsy and in brains from mice with chronic reoccurring seizures. Saturation experiments revealed a KD around 4 nM for the human temporal cortex and 7 nM for the mouse brain. In the human brain, binding of [3H]T-401 was detected mostly in the grey matter, and in the subcortical white matter in lower amounts. The levels were strongly correlated in the two cortical compartments. The level of [3H]T-401 binding in the human temporal cortex varied about a 4-fold among the patients, but was not correlated to either epilepsy duration or the age of the patients. In the epileptic mouse brain, a significant reduction was observed bilaterally in the hippocampus, as well as in other cortical regions, including the temporal cortex. Interestingly, a highly significant negative correlation was seen between MAGL and binding to the translocator protein 18 kDa (TSPO) expressed in glia. These data support the presence of MAGL in neuronal and non-neuronal cells, and indicate that MAGL levels in the brains of either patients with epilepsy or mice after intra-hippocampal kainite injection are reduced not only in the epileptic zone in the hippocampus, but more widespread in the brain.

neuroscience↗

bioRxiv2022

Early impairments of visually-driven neuronal ensemble dynamics in the rTg4510 tauopathy mouse model

Tau protein pathology is a hallmark of many neurodegenerative diseases, including Alzheimers Disease or frontotemporal dementia. Synaptic dysfunction and abnormal visual evoked potentials have been reported in murine models of tauopathy, but little is known about the state of the network activity on a single neuronal level prior to brain atrophy. In the present study, oscillatory rhythms and single-cell calcium activity of primary visual cortex pyramidal neuron population were investigated in basal and light evoked states in the rTg4510 tauopathy mouse model prior to neurodegeneration. We found a decrease in their responsivity and overall activity which was insensitive to GABAergic modulation. Despite an enhancement of basal state coactivation of cortical pyramidal neurons, a loss of input-output synchronicity was observed. Spectral power analysis revealed a reduction of basal theta oscillations in rTg4510 mice. Enhanced susceptibility to a sub-convulsive dose of pentylenetetrazol was further indicated by an increase in theta power and higher number of absence-like seizures in rTg4510 compared to control mice. Our results unveil impairments in visual cortical pyramidal neuron processing and define aberrant oscillations as a biomarker candidate in early stages of neurodegenerative tauopathies.

neuroscience↗

bioRxiv2022

Visual evoked potentials as an early-stage biomarker in the rTg4510 tauopathy mouse model

Tauopathies such as Alzheimers Disease (AD) and frontotemporal dementia (FTD) are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau protein. Early pathophysiological and functional changes related to neurofibrillary tangles formation are considered to occur prior to extensive neurodegeneration. Hyperphosphorylated tau has been detected in postmortem retinas of AD and FTD patients, and the visual pathway is an easily accessible system in a clinical setting. Hence, assessment of the visual function may offer the potential to detect consequences of early tau pathology in patients. In this study we explored the association between the visual system and functional consequences of tau pathology progression using a tauopathy rTg4510 mouse model. To this end, we recorded full-field electroretinography and visual evoked potentials in anesthetized and awake states at different ages. While retinal function remained mostly intact within all the age groups investigated, we detected significant changes in amplitudes of visual evoked potential responses in young rTg4510 mice exhibiting early tau pathology prior to neurodegeneration. These functional alterations in the visual cortex were positively correlated with pathological tau levels. Our findings suggest that visual processing could be useful as a novel electrophysiological biomarker for early stages of tauopathy.

neuroscience↗