Biology subjects

Sensi, S. L.

Publications and source records attributed to Sensi, S. L..

10 recordsLinked to original sources

bioRxiv2026

Analysis of the off-target interaction of amyloid PET tracers with human brain sulfotransferases

Positron emission tomography (PET) tracers targeting amyloid-{beta} (A{beta}) are central to the diagnosis and staging of Alzheimer's disease (AD). However, growing evidence indicates that these tracers can engage off-target molecules, complicating signal interpretation. Sulfotransferases (SULTs) have been experimentally identified as binding partners of 11C-Pittsburgh Compound-B (PiB). However, whether the clinically used fluorinated PiB derivatives flutemetamol and flutafuranol interact with brain-expressed SULTs is yet unexplored. Here, we combined multi-omic transcriptomic profiling with molecular docking and molecular dynamics (MD) simulations to assess the structural interactions of SULT-tracer complexes. Analysis of the Genotype-Tissue Expression project and the Human Protein Atlas identified SULT1A1, SULT1A3, and SULT4A1 as the SULT isoforms predominantly expressed in the human brain. Docking and MD simulations showed that all three tracers form energetically comparable complexes within the catalytic pockets of these isoforms, yet their dynamic stability varied in an enzyme- and tracer-specific manner. PiB and flutemetamol were stably accommodated in SULT1A1, but PiB lost its initial pose in SULT4A1. Flutafuranol showed weaker binding in SULT1A1, yet formed stable complexes in SULT1A3 and SULT4A1. Notably, SULT1A1, SULT1A3, and SULT4A1 are all expressed in the cerebellum, the brain region used as a reference for A{beta} PET signal normalization. These findings provide a structural framework for off-target tracer interaction with brain SULTs and suggest that the intracellular enzymatic environment may contribute to variability in A{beta} PET signals beyond fibrillar A{beta} deposition.

neuroscience↗

bioRxiv2025

Off-target interaction of the amyloid PET imaging tracer PiB with acetylcholinesterase

Pittsburgh compound B (PiB) is a widely used Positron Emission Tomography (PET) tracer for detecting amyloid-{beta} (A{beta}) deposits in Alzheimers disease (AD). While PiB is assumed to bind selectively to A{beta}, emerging evidence suggests off-target interactions that may complicate PET signal interpretation. Here, we report that PiB can interact with acetylcholinesterase (AchE), a key enzyme in the cholinergic system. Similarity screening identified the AchE ligand thioflavin T (ThT) as the top structural analog of PiB. Docking studies and molecular dynamics simulations showed that PiB stably binds the peripheral anionic site (PAS) of AchE, with binding energies comparable to ThT and clinically relevant AchE inhibitors. In vitro fluorescence-based assays confirmed this interaction and suggest an involvement of the PAS. These findings indicate a stable off-target interaction between PiB and AChE with implications for interpreting PiB-PET signals in AD, particularly in regions with altered AchE expression or under AchE inhibitor therapy.

neuroscience↗

bioRxiv2024

ER and SOCE Ca2+ signals are not required for directed cell migration in human microglia

The central nervous system (CNS) is constantly surveilled by microglia, highly motile and dynamic cells deputed to act as the first line of immune defense in the brain and spinal cord. Alterations in the homeostasis of the CNS are detected by microglia that respond by migrating toward the affected area. Understanding the mechanisms controlling directed cell migration of microglia is crucial to dissect their responses to neuroinflammation and injury. We used a combination of pharmacological and genetic approaches to explore the involvement of calcium (Ca2+) signaling in the directed migration of induced pluripotent stem cell (iPSC)-derived microglia challenged with a purinergic stimulus. This approach mimics cues originating from injury of the CNS. Unexpectedly, simultaneous imaging of microglia migration and intracellular Ca2+ changes revealed that this phenomenon does not require Ca2+ signals generated from the endoplasmic reticulum (ER) and store-operated Ca2+ entry (SOCE) pathways. Instead, we find evidence that human microglial chemotaxis to purinergic signals is mediated by cyclic AMP in a Ca2+-independent manner. These results challenge prevailing notions, with important implications in neurological conditions characterized by perturbation in Ca2+ homeostasis.

neuroscience↗

bioRxiv2022

Mapping Pharmacologically-induced Functional Reorganisation onto the Brain's Neurotransmitter Landscape

To understand how pharmacological interventions can exert their powerful effects on brain function, we need to understand how they engage the brains rich neurotransmitter landscape. Here, we bridge microscale molecular chemoarchitecture and pharmacologically-induced macroscale functional reorganisation, by relating the regional distribution of 19 neurotransmitter receptors and transporters obtained from Positron Emission Tomography, and the regional changes in functional MRI connectivity induced by 10 different mind-altering drugs: propofol, sevoflurane, ketamine, LSD, psilocybin, DMT, ayahuasca, MDMA, modafinil, and methylphenidate. Our results reveal that psychoactive drugs exert their effects on brain function by engaging multiple neurotransmitter systems. The effects of both anaesthetics and psychedelics on brain function are organised along hierarchical gradients of brain structure and function. Finally, we show that regional co-susceptibility to pharmacological interventions recapitulates co-susceptibility to disorder-induced structural alterations. Collectively, these results highlight rich statistical patterns relating molecular chemoarchitecture and drug-induced reorganisation of the brains functional architecture.

neuroscience↗

bioRxiv2022

Long-term dynamic changes of NMDA receptors following an excitotoxic challenge

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons [also known as nNOS (+) neurons] are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a key divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we demonstrate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.

neuroscience↗

bioRxiv2019

Inhibition of de novo ceramide biosynthesis affects aging phenotype in an in vitro model of neuronal senescence

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimers disease, Parkinsons disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.\n\nIn this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of de novo ceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as an in vitro model of cellular senescence. Our findings indicate that aged neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca2+]i levels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 {micro}M) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca2+]i signaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.\n\nThe results suggest that the de novo ceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.

neuroscience↗

bioRxiv2018

Exenatide reverts the high-fat-diet-induced impairment of BDNF signaling and inflammatory response in an animal model of Alzheimer’s disease

Backgroundpreclinical, clinical, and epidemiological evidence support the notion that Alzheimers disease(AD) is a multifactorial condition in which, along with {beta}-amyloid (A{beta}) and tau-related pathology, the synergistic activity of genetic, environmental, vascular, metabolic, and inflammatory factors promote the onset and progression of the disease. Epidemiological evidence indicate that glucose intolerance, deficits in insulin secretion or type 2 diabetes mellitus (T2DM) participate in increasing the risk of developing cognitive impairment or dementia. A pivotal role in the process is played by insulin as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a GLP-1R agonist, characterized by an extended half-life, employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models of brain aging and neurodegeneration.\n\nMethodsin this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. To that aim, we investigated the effects of 3-month exenatide treatment in 3xTg-AD mice challenged for six months with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, levels of A{beta} and tau pathology as well as changes in cognitive performances.\n\nFindings and interpretationresults of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD.

neuroscience↗

bioRxiv2018

Elevated plasma ceramide levels in post-menopausal women

Circulating ceramide levels are abnormally elevated in age-dependent pathologies such as cardiovascular diseases, obesity and Alzheimers disease. Nevertheless, the potential impact of age on plasma ceramide levels has not yet been systematically examined. In the present study, we quantified a focused panel of plasma ceramides and dihydroceramides in a cohort of 164 subjects (84 women) 19 to 80 years of age. After adjusting for potential confounders, multivariable linear regression analysis revealed a positive association between age and ceramide (d18:1/24:0) ({beta} (SE) = 5.67 (2.38); p = .0198) and ceramide (d18:1/24:1) ({beta} (SE) = 2.88 (.61); p < .001) in women, and between age and ceramide (d18:1/24:1) in men ({beta} (SE) = 1.86 (.77); p = .0179). In women of all ages, but not men, plasma ceramide (d18:1/24:1) was negatively correlated with plasma estradiol (r = -0.294; p = .007). Finally, in vitro experiments in human cancer cells expressing estrogen receptors showed that incubation with estradiol (10 nM, 24 h) significantly decreased ceramide accumulation. Together, the results suggest that aging is associated with an increase in circulating ceramide levels, which in post-menopausal women may be at least partially dependent on lower estradiol levels.

biochemistry↗

bioRxiv2018

Functional signature of conversion in Mild Cognitive Impairment patients

The entorhinal-hippocampal circuit is a strategic hub for memory but also the first site to be affected in the Alzheimers Disease (AD)-related pathology. We investigated MRI patterns of brain atrophy and functional connectivity in a study cohort obtained from the Alzheimers Disease Neuroimaging Initiative database including healthy control (HC), Mild Cognitive Impairment (MCI), and AD subjects. MCI individuals were clinically evaluated 24 months after the MRI scan, and the group further divided into a subset of subjects who either did (c-MCI) or did not (nc-MCI) convert to AD. Compared to HC subjects, AD patients exhibited a collapse of long-range connectivity from the hippocampus and entorhinal cortex, pronounced cortical/sub-cortical atrophy, and a dramatic decline in cognitive performances. c-MCI patients showed entorhinal and hippocampal hypo-connectivity, no signs of cortical thinning but evidence of right hippocampus atrophy. On the contrary, nc-MCI patients showed lack of brain atrophy, largely preserved cognitive functions, hippocampal and entorhinal hyper-connectivity with selected neocortical/sub-cortical regions mainly involved in memory processing and brain meta-stability. This hyper-connectivity can represent an early compensatory strategy to overcome the progression of cognitive impairment. This functional signature can also be employed for the diagnosis of c-MCI subjects.

neuroscience↗

bioRxiv2018

The pharmacological perturbation of brain zinc impairs BDNF-related signalling and the cognitive performances of young mice

Zinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+ levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+ affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+ levels, we employed the Zn2+ (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signalling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+ was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo.\n\nOur study highlights the importance of choosing \"when\", \"where\", and \"how much\" in the modulation of brain Zn2+ levels. Our findings confirm the importance of targeting Zn2+ as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+ availability upon the early stages of development.

neuroscience↗