Biology subjects

Arancio, O.

Publications and source records attributed to Arancio, O..

11 recordsLinked to original sources

bioRxiv2025

Long-term Locus Coeruleus Stimulation Exacerbates Tau Pathology in PS19 Mice

BackgroundAlzheimers disease (AD) is the most common form of dementia, characterized by the accumulation of amyloid-{beta} (A{beta}) plaques and hyperphosphorylated Tau tangles. The locus coeruleus (LC) is among the first brain regions to show degeneration and Tau pathology during the early stages of AD. Previous studies have demonstrated that short-term chemogenetic LC stimulation can improve memory performance in the TgF344-AD rat model, while long-term norepinephrine (NE) reuptake inhibition can worsen memory deficits in the ADLPTau mouse model. However, the effects of long-term LC stimulation in Tau mouse models on memory, synaptic plasticity, and tauopathy remain unclear. ObjectiveTo evaluate the impact of long-term locus coeruleus stimulation on memory, synaptic plasticity, and tauopathy in PS19 mice using behavioral paradigms, electrophysiological recordings, and immunohistochemical analysis. MethodsThe radial arm water maze and fear conditioning test were conducted to assess memory performance in PS19 mice with and without long-term LC stimulation. Hippocampal long-term potentiation was recorded to evaluate the effect of long-term LC stimulation on synaptic plasticity. Immunohistochemistry was employed to examine Tau phosphorylation, neurodegeneration, and neuroinflammation. ResultsLong-term LC stimulation in PS19 mice exacerbated spatial memory deficits in the water maze, impaired contextual fear memory, reduced hippocampal LTP, and increased AEP expression, Tau hyperphosphorylation, and astrocyte activation. ConclusionLong-term LC stimulation may exacerbate memory deficits in PS19 mice by impairing synaptic plasticity and increasing neural degeneration in the hippocampus. Elevated norepinephrine levels resulting from long-term LC stimulation may increase AEP expression, contributing to Tau hyperphosphorylation in the LC.

pathology↗

bioRxiv2025

The Highly Selective 5-HT2B Receptor Antagonist MW073 Mitigates Aggressive Behavior in an Alzheimer Disease Mouse Model.

1.Alzheimers disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic and neuronal loss underlies the decline in cognition and daily functioning, often accompanied by behavioral and psychological symptoms. Among these, neuropsychiatric disturbances such as agitation and aggression affect 20-65% of patients and represent a major source of caregiver burden. The serotonin receptor antagonist MW073 has recently emerged as a potential therapeutic candidate, showing efficacy in counteracting A{beta}- and tau-induced synaptic and memory deficits in AD mouse models. Here, we investigated whether MW073 also mitigates aggressive behavior in Tg2576 mice, a widely used AD model that also displays heightened aggressiveness. Our findings demonstrate that MW073 significantly reduced aggressive tendencies in Tg2576 mice, suggesting that serotonergic modulation may represent a promising strategy to address both cognitive and neuropsychiatric symptoms of AD.

neuroscience↗

bioRxiv2025

Epigenetic Shifts Reveal Alzheimer's Origins after Sustained Picomolar Aβ Exposure

Recent advances in sequencing have identified genetic risk factors for Alzheimers disease (AD), but the molecular mechanisms triggering disease onset remain unclear. While high brain levels of amyloid-beta (A{beta}) impair synaptic function and memory, exposure to low picomolar (pM) A{beta} concentrations - typical of healthy brains - enhances these functions, while sustained exposure results in impairment. To investigate this transition from physiological to pathological A{beta} activity, we profiled DNA methylation and gene expression in C57B16 mice subjected to prolonged pM A{beta}42 exposure. We identified differentially methylated and expressed genes, including those involved in synaptic function, associated with three phases: memory enhancement (brief exposure), a transitional state with intact memory (intermediate), and memory decline (prolonged). These gene sets may represent early molecular drivers of AD pathogenesis.

neuroscience↗

bioRxiv2025

PP2A METHYLESTERASE, PME-1, AND PP2A METHYLTRANSFERASE, LCMT-1, CONTROL SENSITIVITY TO IMPAIRMENTS CAUSED BY INJURY-RELATED OLIGOMERIC TAU

Oligomeric species of tau are a hallmark of multiple neurodegenerative diseases such as Alzheimers disease (AD) and chronic traumatic encephalopathy (CTE). Given the evidence implicating protein phosphatase 2A (PP2A) in the molecular pathogenesis of tau-related neurodegenerative disorders, we sought to determine whether manipulating the expression of enzymes that regulate PP2A activity, such as leucine carboxyl methyltransferase 1 (LCMT-1) and protein methyl esterase 1 (PME-1), might impact pathological responses to oligomeric tau. Here, we tested the effect of transgenic overexpression of LCMT-1 or PME-1 on cognitive and electrophysiological impairments caused by exposure to either recombinant oligomeric human tau or oligomeric tau prepared from mice subjected to blast-induced traumatic brain injury. We found that overexpression of LCMT-1 reduced sensitivity to tau-induced impairments, while overexpression of PME-1 increased sensitivity to these impairments. Moreover, we found that shockwave exposure increased the propensity of endogenous tau to form toxic oligomers. These results suggest that manipulating LCMT-1 or PME-1 activity may represent novel therapeutic approaches for disorders involving exposure to pathogenic forms of oligomeric tau.

neuroscience↗

bioRxiv2025

Design and Synthesis of Potent First-in-Class Histones Acetyltransferase Modulators.

Epigenetic regulation governs gene expression through histone modifications, particularly the acetylation of lysine residues. These modifications are orchestrated by enzymes such as histone acetyltransferases (HATs) and histone deacetylases (HDACs). Among them, p300 plays a critical role in various disorders such as neurodegenerative conditions (i.e. Alzheimers disease, and Alzheimers Disease related dementia) and cancer (i.e. glioblastoma and B cell lymphoma). Our aim is to develop therapeutic interventions for these ailments. In this context, we designed and synthesized novel activators of the enzyme. Using an in vitro screening approach combined with structural activity relationship analysis, we successfully identified compounds that modulate histone acetylation.

biochemistry↗

bioRxiv2025

Endogenously generated Dutch-type Aβ nonfibrillar aggregates dysregulate presynaptic neurotransmission in the absence of detectable inflammation

Structured AbstractO_ST_ABSBackgroundC_ST_ABSAPPE693Q ("Dutch") transgenic mice develop aging-related learning deficits and accumulate endogenously generated nonfibrillar aggregates of A{beta} (NFA-A{beta}) and APP -carboxy terminal fragments. NFA-A{beta} correlates with synaptic loss and memory deficits more closely than does fibrillar A{beta}. MethodsWe assessed the physiological, transcriptomic, ultrastructural, histological, and metabolic changes associated with the accumulation of NFA of Dutch A{beta} in brains of APPE693Q mice. ResultsAging-related accumulation of NFA-A{beta} in APPE693Q mice was revealed by A11 immunohistochemistry and cyclic D,L--peptide-FITC microscopy. Presynaptic termini of APPE693Q mice developed physiological abnormalities in post-tetanic potentiation, synaptic fatigue, synaptic vesicle replenishment, and an aging-related reduction in mitochondrial complex I activity. Single-cell RNA sequencing showed that excitatory neurons exhibited an altered transcriptomic profile involving "protein translation" and "oxidative phosphorylation". DiscussionAccumulation of NFA-A{beta} alters neuronal metabolism but does not activate inflammation. Depletion of all forms of A{beta} may be required to eliminate A{beta} toxicity with anti-amyloid antibodies.

neuroscience↗

bioRxiv2023

Stimulation of mRNA translation rescues hippocampal synaptic plasticity and memory in mouse models of Alzheimer's disease

Impaired synaptic plasticity and progressive memory deficits are major hallmarks of Alzheimers disease (AD). Hippocampal mRNA translation, required for memory consolidation, is defective in AD. Here, we show that systemic treatment with (2R,6R)- hydroxynorketamine (HNK), an active metabolite of the antidepressant ketamine, prevented deficits in hippocampal mRNA translation, long-term potentiation (LTP) and memory induced by AD-linked amyloid-{beta} oligomers (A{beta}Os) in mice. HNK activated hippocampal extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 (S6), which promote protein synthesis and synaptic plasticity. Stimulation of S6 phosphorylation by HNK was mTORC1-dependent, while rescue of hippocampal LTP and memory in HNK-treated A{beta}O-infused mice was ERK1/2-dependent and, partially, mTORC1- dependent. Remarkably, treatment with HNK corrected LTP and memory deficits in aged APP/PS1 mice. Transcriptomic analysis further showed that HNK rescued signaling pathways that are aberrant in APP/PS1 mice, including inflammatory and hormonal responses, and programmed cell death. Taken together, our findings demonstrate that HNK induces signaling and transcriptional responses that correct deficits in hippocampal synaptic plasticity and memory in AD mouse models. These results raise the prospect that HNK could serve as a therapeutic to prevent or reverse memory decline in AD.

neuroscience↗

bioRxiv2022

SUMO2 Protects Against Tau-induced Synaptic and Cognitive Dysfunction

Abnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimers disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD), which can be caused by mutations of Tau. Mutated and pathological Tau can undergo a range of post-translational modifications (PTMs) that might trigger or modulate disease pathology. Recent studies indicate that modification of wild type Tau by Small ubiquitin-like modifier SUMO isoform 1 (SUMO1) controls Tau hyperphosphorylation and aggregation, suggesting that SUMOylation acts as a central regulator of Taus biochemical properties. Besides SUMO1, Tau is modified by SUMO2/3, however the consequences of this modification have not been investigated. Here, using viral approaches on primary hippocampal neurons, transgenic mice expressing mutant Tau and SUMO2, and iPSC-derived neurons from FTD patients, we evaluated whether SUMO2/3 conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant Tau P301L, P301S, and R406W variants. We found that mutant forms of Tau are targets of SUMO2/3, and SUMO2/3 conjugation is neuroprotective. Importantly, expression of mutant Tau is accompanied by a significant reduction of SUMO2/3 conjugation levels, and restoring levels of SUMO2 reduces mutant Tau aggregation and phosphorylation in all model systems Furthermore, overexpression of SUMO2 restores levels of pre- and post-synaptic markers, associated with a complete rescue of the LTP and memory deficits in transgenic mice expressing mutant Tau. These findings bring to light the potential therapeutic implication of manipulating SUMO conjugation to detoxify Tau through PTM-based approaches.

neuroscience↗

bioRxiv2022

AAV-mediated neuronal expression of a scFv antibody selective for Aβ oligomers protects synapses and rescues memory in Alzheimer models

Brain accumulation of soluble oligomers of the amyloid-{beta} peptide (A{beta}Os) has been implicated in synapse failure and memory impairment in Alzheimers disease. Here, we show that treatment with NUsc1, a single-chain variable fragment antibody (scFv) that selectively targets A{beta}Os, prevents the inhibition of long-term potentiation in hippocampal slices and memory impairment induced by A{beta}Os in mice. As a therapeutic approach for intracerebral antibody delivery, we developed an adeno-associated virus vector to drive neuronal expression of NUsc1 (AAV-NUsc1) within the brain. Transduction by AAV-NUsc1 induced NUsc1 expression and secretion in adult human brain slices, and inhibited A{beta}O binding to neurons and A{beta}O-induced loss of dendritic spine loss in primary rat hippocampal cultures. Treatment of mice with AAV-NUsc1 prevented memory impairment induced by A{beta}Os and, importantly, reversed memory deficits in aged APPswe/PS1{Delta}E9 Alzheimers disease model mice. These results support the feasibility of gene-mediated immunotherapy using single-chain antibodies as a potential therapeutic approach in Alzheimers disease.

neuroscience↗

bioRxiv2021

A failure of β-amyloid physiological function due to genetic deletion of α7 nicotinic acetylcholine receptors induces an Alzheimer's disease-like pathology

The accumulation of amyloid-beta peptide (A{beta}) and the failure of cholinergic transmission are key players in Alzheimers disease (AD). However, in the healthy brain, A{beta} contributes to synaptic plasticity and memory acting through 7 subtype nicotinic acetylcholine receptors (7nAChRs). Here, we hypothesized that the 7nAChR deletion blocks A{beta} physiological function and promotes a compensatory increase in A{beta} levels that, in turn, triggers an AD-like pathology. To validate this hypothesis, we studied the age-dependent phenotype of 7 knock out mice. We found that 7nAChR deletion caused an impairment of hippocampal synaptic plasticity and memory at 12 months of age, paralleled by an increase of Amyloid Precursor Protein expression and A{beta} levels. This was accompanied by other classical AD features such as a hyperphosphorylation of tau at residues Ser 199, Ser 396, Thr 205, a decrease of GSK-3{beta} at Ser 9, the presence of paired helical filaments and neurofibrillary tangles, neuronal loss and astrocytosis. Our findings suggest that 7nAChR malfunction might precede A{beta} and tau pathology, offering a different perspective to interpret the failure of anti-A{beta} therapies against AD and to find novel therapeutical approaches aimed at restoring 7nAChRs-mediated A{beta} function at the synapse.

neuroscience↗

bioRxiv2020

ECSIT prevents Alzheimer's disease pathology by regulating neuronal mitochondrial ROS and mitophagy

Altered mitochondrial fitness is a potential triggering factor in Alzheimers disease (AD). Mitochondrial quality control pathways are dysfunctional and mitochondrially-derived reactive oxygen species (mROS) levels are increased in AD patient brains. However, the pathways responsible for dysregulated mROS accumulation have remained relatively unclear. In this study, we demonstrate that levels of ECSIT, a mitochondrial oxidative phosphorylation (OxPhos) complex I (CI)-associated protein, are reduced in AD-affected brains. Neuronal ECSIT downregulation increased mROS generation and impaired mitophagy of defective mitochondria. Consequently, decreasing neuronal ECSIT caused AD-like changes, including memory loss and neuropathology. In contrast, augmented neuronal expression of ECSIT protected against the development of an AD-like phenotype. Decreased levels of ECSIT in AD patient brains therefore likely contribute to oxidative stress, neuroinflammation and AD pathogenesis.

neuroscience↗