About

Ottavio Arancio, MD, PhD, is a Professor of Pathology and Cell Biology and of Medicine at Columbia University, affiliated with the Taub Institute for Research on Alzheimer's Disease and the Aging Brain. He received his MD and PhD from the University of Pisa in Italy and completed residency training in Neurology at the University of Verona. Dr. Arancio has held faculty appointments at Columbia University, NYU School of Medicine, and SUNY HSCB. Since 2004, he has been a faculty member at Columbia University, where he is involved in research and teaching. His research focuses on the mechanisms of synaptic plasticity, particularly how oligomeric proteins such as amyloid-beta and tau interfere with memory formation and hippocampal long-term potentiation, which are models of learning and memory. Dr. Arancio is a cellular neurobiologist who has contributed to understanding the cellular and molecular mechanisms underlying learning in both healthy brains and in neurodegenerative diseases, especially Alzheimer's disease. Over the past decade, he has pioneered research into synaptic dysfunction in Alzheimer’s disease and has established a mouse model for traumatic brain injury using shockwave exposure. His laboratory investigates how changes in gene activation, post-translational mechanisms, ion channel activity, calcium signaling, and transmitter release contribute to synaptic function and dysfunction. Dr. Arancio has published extensively, raised significant grant funding, and is recognized for his contributions to neurobiology, neurodegeneration, and the understanding of learning and memory.

Research topics

• Neuroscience
• Cell biology
• Medicine
• Biochemistry
• Biology
• Internal medicine
• Immunology
• Psychology
• Pharmacology
• Chemistry

Selected publications

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

  Cells · 2026-02-01

  articleOpen accessSenior authorCorresponding

  Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40–60% of patients and represent a major source of caregiver burden. Serotonin 5-HT2B receptor levels are increased in the AD patient brain, and thus, treatment of AD animal models with the selective 5-HT2B receptor antagonist MW073 in prevention or disease stage paradigms attenuates Aβ- or tau-induced dysfunction. Methods: We investigated the effects of MW073 treatment on the aggressive behavior of Tg2576 mice in a resident–intruder assay. Results: MW073 treatment significantly reduced aggressive behavior in male Tg2576 mice. Conclusions: MW073 efficacy in treating aggression in Tg2576 mice implicates 5-HT2B receptor-mediated signaling in AD neuropsychiatric symptoms as well as cognitive and behavioral dysfunction.

  PublisherOA PDFDOI

• Angiopoietin-2 aggravates Alzheimer’s disease by promoting blood-brain barrier dysfunction and neuroinflammation

  Cell Reports · 2026-01-01 · 2 citations

  articleOpen access

  Disruption of the blood-brain barrier (BBB) increases vascular permeability and promotes neuroinflammation, contributing to Alzheimer's disease (AD) progression. However, the molecular drivers of BBB dysfunction and neuroinflammation in AD remain poorly defined. Here, we identify angiopoietin-2 (ANGPT2) as a central mediator of BBB breakdown and AD progression. Transcriptomic analyses of human AD brains revealed elevated ANGPT2 expression in endothelial cells correlating with disease severity. In 5xFAD mice, endothelial-specific Angpt2 deletion reduced β-amyloid deposition, while Angpt2 overexpression via an adeno-associated viral vector exacerbated the plaque burden. Mechanistically, ANGPT2 suppression of TIE2 signaling increased vascular leakage and fibrin deposition, triggering microglial activation and neuroinflammatory responses that accelerated disease progression. Single-nucleus transcriptomic analyses further revealed Angpt2-driven microglial dysfunction and neuronal impairment consistent with memory deficits observed in behavioral assays. These findings establish ANGPT2 as a critical driver of BBB dysfunction and neuroinflammation in AD and highlight its therapeutic potential.

  PublisherDOI

• Synaptic plasticity deficits in a mouse model of Timothy syndrome: LTP saturation and its pharmacological rescue by nifedipine

  Biomedicine & Pharmacotherapy · 2025-02-11 · 2 citations

  articleOpen access

  Timothy syndrome (TS) is a multisystem disorder characterized by cardiovascular abnormalities and a spectrum of neuropsychiatric symptoms, including language impairment, seizure, cognitive disability and autism. TS is caused by gain of function mutations in the CACNA1C gene that encodes the CaV1.2 L-type calcium channel. TS mutations have been reported to disrupt hippocampal long-term potentiation (LTP), a process implicated in memory formation. Here, we compared wild type (WT) and heterozygous G406R CaV1.2 mutant TS2-neo model mice using a LTP saturation protocol consisting of two successive theta burst stimuli. While WT mice showed potentiated synaptic strength in response to both theta-burst stimuli, TS2-neo mutants exhibited a smaller initial LTP and minimal responses to the second stimulus. The dihydropyridine L-type calcium channel blocker, nifedipine, inhibited LTP in WT mice, but enhanced both the initial and the second LTP in TS2-neo mutants. By measuring the phosphorylation activation of ERK, CREB and glutamate receptor GluR1, steps required for hippocampal LTP, we found that all were abnormally high at baseline in the mutant mice. Nifedipine blocked LTP-related phosphorylation in WT mice, but normalized baseline phosphorylation of ERK, CREB and GluR1 in TS2-neo mice, allowing their subsequent activity-dependent induction. Thus, while nifedipine inhibits LTP in WT mice, the drug reinstates LTP and normal synaptic plasticity in a TS model, suggesting potential therapeutic approaches for synaptic deficits in channelopathies such as TS. • The calcium channel activity of CaV1.2 is upregulated by the G406R mutation. • TS2-neo mice show impaired TBS-LTP associated with abnormal LTP saturation. • TS2-neo mice show high baseline phosphorylation of ERK, CREB and GluR1. • Nifedipine normalizes baseline phosphorylation of calcium regulated signal pathways in TS2-neo mice. • Nifedipine reinstates normal synaptic plasticity in TS2-neo mice.

  PublisherDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-11-03

  preprintOpen access

  Abstract Background Alzheimer’s disease (AD) is the most common form of dementia, characterized by the accumulation of amyloid-β (Aβ) 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 ADLP Tau mouse model. However, the effects of long-term LC stimulation in Tau mouse models on memory, synaptic plasticity, and tauopathy remain unclear. Objective To 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. Methods The 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. Results Long-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. Conclusion Long-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.

  PublisherOA PDFDOI

• Discovery of small molecule candidate therapeutics against neuroimmune targets in Alzheimer’s disease

  Alzheimer s & Dementia · 2025-12-01

  articleOpen access

  BACKGROUND: Dysregulated brain inflammation is a critical mechanism driving neurodegenerative disease progression. Neuroinflammatory processes are fundamental to CNS homeostasis, but inflammation that is inefficient, excessive, or prolonged is detrimental. Stressor-induced proinflammatory cytokine overproduction is an explicit form of neuroinflammation linked to activated glia and synaptic dysfunction in Alzheimer's disease (AD). We have explored pharmacological mechanisms that could attenuate dysregulated proinflammatory cytokine production and restore glia-neuronal homeostasis. We used both unbiased phenotypic and single molecular target approaches to discover and develop unique therapeutic candidates that selectively modulate panels of proinflammatory cytokines linked to pathophysiology susceptibility or progression. METHOD: We designed and synthesized strategic collections of unique small molecules based on the privileged pyridazine chemotype and pharmacoinformatics. Recursive screens and medicinal chemistry refinements were driven by secondary pharmacology assays integrated with in vivo efficacy and pharmacodynamics measurements in diverse animal models. The independent parallel approaches delivered a series of candidates for disease-focused development. All deliverables exhibited oral bioavailability and brain exposure, promising safety profiles, and efficacy at low doses in animal models of CNS disorders. RESULT: Three therapeutic candidates, MW150, MW151, and MW189, are in human phase 1b/2a clinical trials. CONCLUSION: Our drug discovery efforts have taught us several important lessons: 1) Focus efforts on disease-relevant pathophysiology processes integrated with strategic compound design. 2) Fail fast and early. 3) Complex diseases such as AD require interventions that target complementary disease drivers and therapeutic intervention time windows. 4) Dosing is the pharmacological basis of successful therapeutic intervention: what, when, and how - the RIGHT drug(s) at the RIGHT time(s) for the RIGHT disease mechanism. 5) The cytokine/synaptic dysfunction axis is a viable pathophysiology process for therapeutic intervention where proinflammatory cytokine dysregulation is part of the disease progression mechanism.

  PublisherOA PDFDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-05 · 1 citations

  preprintOpen access

  ABSTRACT 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. Alzheimer’s disease, and Alzheimer’s 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.

  PublisherOA PDFDOI

• Optimized 5‐HT _2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction

  Alzheimer s & Dementia Translational Research & Clinical Interventions · 2025-01-01 · 1 citations

  articleOpen access

  Abstract INTRODUCTION Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non‐pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5‐HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5‐HT 2b receptor (5‐HT 2b R) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post‐stroke morbidity. HTR2B gene variants are implicated in psychiatric disorders. 5‐HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5‐HT 2b R inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5‐HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5‐HT 2b R inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia. METHODS Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5‐HT 2b R activity and β‐arrestin‐1 recruitment that is devoid of dopamine receptor recognition and risk of 5‐HT 2b R agonist activity. RESULTS MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose‐dependent inhibitor 5‐HT 2b R activity and β‐arrestin‐1 recruitment. DISCUSSION Selective inhibition of 5‐HT 2b R activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics. Highlights A new highly selective 5‐HT 2b R antagonist, MW073, is described and used as a reference standard. MW073 attenuates synaptic and behavioral dysfunctions an animal models of neuropsychatric syndromes. Risperidone is a dose dependent inhibitor of 5‐HT 2b R activity and arrestin recruitment.

  PublisherOA PDFDOI

• Systems-Level Interactome Mapping Reveals Actionable Protein Network Dysregulation Across the Alzheimer's Disease Spectrum

  Research Square · 2025-02-12 · 1 citations

  preprintOpen accessSenior author
  PublisherDOI

• Bench to Bedside Using the iSAFE Discovery and Development Platform for CNS Protein Kinase Inhibitors: A Phase 2 Clinical Asset Example (Abstract ID: 170677)

  Journal of Pharmacology and Experimental Therapeutics · 2025-03-01

  article
  PublisherDOI

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

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-21

  preprintOpen accessSenior authorCorresponding

  1. ABSTRACT Alzheimer’s 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 Aβ- 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.

  PublisherOA PDFDOI

Recent grants

• NIH Grant RF1AG055125

  NIH · $2.0M · 2023

• Chaperome networks in Alzheimer's disease

  NIH · $5.9M · 2021–2027

• NIH Grant U01AG032973

  NIH · $1.1M · 2014

• NIH Grant R21AG027468

  NIH · $372k · 2010

• NIH Grant U01AG028713

  NIH · $2.1M · 2012

Frequent coauthors

• Daniela Puzzo

  Istituti di Ricovero e Cura a Carattere Scientifico

  70 shared

• Fortunato Battaglia

  Hackensack Meridian Health

  48 shared

• Fabrizio Trinchese

  42 shared

• Agnieszka Staniszewski

  Columbia University

  41 shared

• Michael L. Shelanski

  Columbia University

  38 shared

• Bing Gong

  33 shared

• Mauro Fà

  Columbia University

  33 shared

• Agostino Palmeri

  University of Catania

  32 shared

Labs

• Digital and Computational Pathology LaboratoryPI

  The Digital and Computational Pathology Laboratory focuses on the development and application of computational methods to improve the diagnosis and treatment of diseases.

Education

• M.D., Medicine

  Columbia University

• Ph.D.

  Columbia University

Awards & honors

• G. Moruzzi Fellowship (1987)
• Anna Villa Rusconi Foundation Prize (1990)
• INSERM Poste Vert Fellowship (1991)
• Fellowship, University of Bologna (1994)
• Whitehead Fellowship (2001-2003)