Biology subjects

Bentivegna, M.

Publications and source records attributed to Bentivegna, M..

2 recordsLinked to original sources

bioRxiv2026

Differential Effects of Neutral Sphingomyelinase and Serine Palmitoyltransferase Inhibitors on Alzheimer's-Like Neuropathology.

Alzheimer's disease (AD) involves progressive neurodegeneration, amyloid-{beta} (A{beta}) pathology and chronic neuroinflammation. Elevated ceramides, generated via neutral sphingomyelinase (nSMase)-mediated sphingomyelin hydrolysis or serine palmitoyltransferase (SPT)-driven de novo synthesis, amplify these processes. Here, we performed a direct comparison of pharmacological inhibition of these pathways in the PDAPP-J20 transgenic mouse model and in fibrillized A{beta}1-42-challenged BV-2 murine microglial cell line. Eight-month-old PDAPP-J20 female mice received intraperitoneal GW4869 (nSMase inhibitor, 1.25 mg/kg) or myriocin (SPT inhibitor, 0.3 mg/kg) three times weekly for 3 weeks. Neutral SMase inhibition restored spatial learning in the Barnes maze, reduced hippocampal neuronal loss and layer atrophy, decreased amyloid plaque burden, and attenuated microglial activation (Iba1 morphology and peri-plaque reactivity). In contrast, SPT inhibition worsened thigmotaxis, failed to improve cognition, and increased plaque load. In vitro, nSMase blockade (GW4869 and cambinol) suppressed A{beta}-induced NF{kappa}B p65 nuclear translocation, blunted TNF- expression, and reduced intracellular A{beta} accumulation in microglia, suggesting enhanced endolysosomal degradation. SPT inhibition lacked these anti-inflammatory and clearance-promoting effects. These results identify nSMase as a critical node linking ceramide metabolism, microglial dysfunction, and amyloid progression in AD. Targeted nSMase inhibition offers a promising molecular strategy to interrupt neuroinflammation and restore neuronal homeostasis, while broad SPT blockade appears counterproductive. Pathway-selective modulation of ceramide signaling may open new therapeutic avenues for AD.

neuroscience↗

bioRxiv2025

Serotonin signaling in the rat prefrontal cortex is required for Retrieval-Induced Forgetting

Forgetting is a ubiquitous phenomenon actively promoted in many species. The act of remembering some experiences can cause forgetting of others in both humans and rats. We previously found that when rats retrieve a memory to guide exploration, it reduces later retention of other competing memories encoded in that environment. As with humans, this retrieval-induced forgetting (RIF) relies on prefrontal control processes, is competition-dependent, and cue-independent. RIF is thought to be driven by inhibitory control signals from the prefrontal cortex that target areas where memories are stored. Serotonin plays a crucial role in behaviors requiring high cognitive demand, including memory processes, partly through its modulation of prefrontal cortex activity. However, its potential involvement in regulating active forgetting remains unexplored. Here, we had rats perform a task known to induce RIF and pharmacologically manipulated the activity and signaling of serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2C in the medial prefrontal cortex (mPFC), as well as to inhibit downstream effectors. Our findings reveal a specific role for prefrontal serotonin signaling in RIF. Whereas 5-HT2C receptor manipulation had no effect, activating 5-HT1A or blocking 5-HT2A receptors in the mPFC abolished RIF. By contrast, activating 5-HT2A receptors promoted RIF under conditions in which it is normally reduced. Further analyses identified the PI3K/AKT pathway as a downstream effector of 5-HT2A receptor signaling, suggesting a specific molecular mechanism through which serotonin modulates inhibitory control over memory. These results uncover a previously unrecognized serotonergic modulation of adaptive forgetting, identifying specific receptor subtypes that link prefrontal serotonin signaling to inhibitory control over memory competition.

animal behavior and cognition↗