Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer’s disease

Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer’s disease. The degeneration of cholinergic neurons is a prominent feature of Alzheimer’s disease (AD). In animal models of injury and aging, nerve growth factor (NGF) enhances cholinergic cell survival and function, contributing to improved memory. In the presence of AD pathology, however, NGF-related therapeutics have yet to fulfill their regenerative potential. We propose that stimulating the TrkA receptor, without p75NTR activation, is key for therapeutic efficacy. Supporting this hypothesis, the selective TrkA agonist D3 rescued neurotrophin signaling in TgCRND8 mice, whereas NGF, interacting with both TrkA and p75NTR, did not. D3, delivered intravenously and noninvasively to the basal forebrain using MRI-guided focused ultrasound (MRIgFUS)–mediated blood-brain barrier (BBB) permeability activated TrkA-related signaling cascades and enhanced cholinergic neurotransmission. Recent clinical trials support the safety and feasibility of MRIgFUS BBB modulation in AD patients. Neuroprotective agents targeting TrkA, combined with MRIgFUS BBB modulation, represent a promising strategy to counter neurodegeneration in AD.

• Publication year

  2020

• Venue

  Science Advances

• Publication date

  2020-01-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.1126/sciadv.aax6646PMID 32010781PMCID 6976301
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• The feasibility study

  2019cited by this paper
• Pharmacological interrogation of TrkA-mediated mechanisms in hippocampal-dependent memory consolidation

  2019cited by this paper
• Evaluating the safety profile of focused ultrasound and microbubble-mediated treatments to increase blood-brain barrier permeability

  2019cited by this paper
• Radioligands for Tropomyosin Receptor Kinase (Trk) Positron Emission Tomography Imaging

  2019cited by this paper
• Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions

  2019cited by this paper
• Adeno-Associated Viral Vector (Serotype 2)–Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial

  2018cited by this paper
• Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound

  2018cited by this paper
• Time course of focused ultrasound effects on β-amyloid plaque pathology in the TgCRND8 mouse model of Alzheimer’s disease

  2018cited by this paper
• The ProNGF/p75NTR pathway induces tau pathology and is a therapeutic target for FTLD-tau

  2018cited by this paper
• Gene Therapy in Alzheimer Disease-It May Be Feasible, but Will It Be Beneficial?

  2018cited by this paper
• Noninvasive delivery of an α‐synuclein gene silencing vector with magnetic resonance–guided focused ultrasound

  2018cited by this paper
• Neurotrophin receptor agonists and antagonists as therapeutic agents: An evolving paradigm.

  2017cited by this paper
• Quantification of brain cholinergic denervation in Alzheimer’s disease using PET imaging with [18F]-FEOBV

  2017cited by this paper
• Acute Inflammatory Response Following Increased Blood-Brain Barrier Permeability Induced by Focused Ultrasound is Dependent on Microbubble Dose

  2017cited by this paper
• Cholinergic neuron gene expression differences captured by translational profiling in a mouse model of Alzheimer's disease.

  2017cited by this paper
• Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

  2016cited by this paper
• Venular degeneration leads to vascular dysfunction in a transgenic model of Alzheimer's disease.

  2015cited by this paper
• Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model

  2015cited by this paper
• Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease.

  2015influential reference
• Alzheimer disease in a mouse model: MR imaging-guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior.

  2014cited by this paper
• Trk receptors.

  2014cited by this paper
• Mast cells on the mind: new insights and opportunities.

  2013cited by this paper
• Safety and efficacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye

  2013cited by this paper
• Amyloid-β plaque reduction, endogenous antibody delivery and glial activation by brain-targeted, transcranial focused ultrasound.

  2013cited by this paper
• Overexpression of the vesicular acetylcholine transporter increased acetylcholine release in the hippocampus.

  2012cited by this paper
• Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller.

  2012cited by this paper
• Hippocampal GABAergic Neurons are Susceptible to Amyloid-β Toxicity in vitro and are Decreased in Number in the Alzheimer's Disease TgCRND8 Mouse Model

  2012cited by this paper
• Targeted Delivery of Neural Stem Cells to the Brain Using MRI-Guided Focused Ultrasound to Disrupt the Blood-Brain Barrier

  2011cited by this paper
• Ligand-Dependent TrkA Activity in Brain Differentially Affects Spatial Learning and Long-Term Memory

  2011cited by this paper
• Chronic and Acute Models of Retinal Neurodegeneration TrkA Activity Are Neuroprotective whereas p75NTR Activity Is Neurotoxic through a Paracrine Mechanism*

  2010cited by this paper
• Microbubble-Size Dependence of Focused Ultrasound-Induced Blood–Brain Barrier Opening in Mice In Vivo

  2010cited by this paper
• Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: experimental study in rats

  2010cited by this paper
• Antibodies Targeted to the Brain with Image-Guided Focused Ultrasound Reduces Amyloid-β Plaque Load in the TgCRND8 Mouse Model of Alzheimer's Disease

  2010cited by this paper
• The p75 Neurotrophin Receptor Promotes Amyloid-β(1-42)-Induced Neuritic Dystrophy In Vitro and In Vivo

  2009cited by this paper
• NGF and BDNF signaling control amyloidogenic route and Aβ production in hippocampal neurons

  2008cited by this paper
• Use of ultrasound pulses combined with Definity for targeted blood-brain barrier disruption: a feasibility study.

  2007cited by this paper
• Nerve growth factor gene delivery: Animal models to clinical trials

  2007cited by this paper
• Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice.

  2006cited by this paper
• Down regulation of trk but not p75NTR gene expression in single cholinergic basal forebrain neurons mark the progression of Alzheimer's disease

  2006cited by this paper
• Nerve growth factor in treatment and pathogenesis of Alzheimer's disease.

  2006cited by this paper
• Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

  2004cited by this paper
• Gene Expression Profiles of Cholinergic Nucleus Basalis Neurons in Alzheimer's Disease

  2002cited by this paper
• Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits.

  2001cited by this paper
• Nontropic actions of neurotrophins: subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation.

  2001cited by this paper
• Early-onset Amyloid Deposition and Cognitive Deficits in Transgenic Mice Expressing a Double Mutant Form of Amyloid Precursor Protein 695*

  2001cited by this paper
• Failed retrograde transport of NGF in a mouse model of Down's syndrome: Reversal of cholinergic neurodegenerative phenotypes following NGF infusion

  2001cited by this paper
• Nerve growth factor signaling, neuroprotection, and neural repair.

  2001cited by this paper
• A designed peptidomimetic agonistic ligand of TrkA nerve growth factor receptors.

  2000cited by this paper
• Phenotypic Knockout of Nerve Growth Factor in Adult Transgenic Mice Reveals Severe Deficits in Basal Forebrain Cholinergic Neurons, Cell Death in the Spleen, and Skeletal Muscle Dystrophy

  2000cited by this paper
• Genuine Monovalent Ligands of TrkA Nerve Growth Factor Receptors Reveal a Novel Pharmacological Mechanism of Action*

  2000cited by this paper
• The Effects of Nerve Growth Factor on Spatial Recent Memory in Aged Rats Persist after Discontinuation of Treatment

  1997cited by this paper
• TrkA activation is sufficient to rescue axotomized cholinergic neurons.

  1996cited by this paper
• Intraparenchymal NGF injections in adult and aged rats induce long-lasting Trk tyrosine phosphorylation.

  1996cited by this paper
• Trophic effect of exogenous nerve growth factor on rat striatal cholinergic neurons: comparison between intraparenchymal and intraventricular administration.

  1996cited by this paper
• Human nerve growth factor improves spatial memory in aged but not in young rats

  1994cited by this paper
• The aged monkey basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor.

  1994cited by this paper
• The cholinergic hypothesis of geriatric memory dysfunction.

  1982cited by this paper
• The randomized clinical trial.

  1972influential reference

• Focused Ultrasound for the Treatment of Circuit and Molecular Pathology in Parkinson's Disease.

  2026cites this paper
• Precise antibody delivery to the brain via nanobubble-actuated focused ultrasound alleviates depression

  2025cites this paper
• THE MODULATION OF THE BLOOD-BRAIN BARRIER BY FOCUSED ULTRASOUND STIMULATES OLIGODENDROGENESIS

  2025cites this paper
• The Application of Ultrasound-Induced Blood-Brain Barrier Opening in Neurology and Immunology.

  2025cites this paper
• Overcoming the Blood-Brain Barrier for Drug Delivery to the Brain

  2025cites this paper
• 2'-Fucosyllactose Ameliorates Cognitive Impairment and Neuroinflammation in AD Mice.

  2025cites this paper
• A Glimpse of the Role of Olfactory Tubercle in Neuropsychiatric Disorders

  2025cites this paper
• Current trends in advanced imaging modalities for the early diagnosis of Alzheimer's disease

  2025cites this paper
• Focused ultrasound-mediated temozolomide delivery into intact blood–brain barrier tissue improves survival in patient-derived xenograft model of glioblastoma

  2025cites this paper
• Implantable hydrogels as pioneering materials for next-generation brain-computer interfaces.

  2025cites this paper
• Selective inhibitors of the TrkC.T1 receptor reduce retinal inflammation and delay neuronal death in a model of retinitis pigmentosa

  2025cites this paper
• Ultrasound Stimulation Modulates Microglia M1/M2 Polarization and Affects Hippocampal Proteomic Changes in a Mouse Model of Alzheimer's Disease

  2024cites this paper
• Progress of research in the application of ultrasound technology for the treatment of Alzheimer’s disease

  2024cites this paper
• Recent advances of focused ultrasound induced blood-brain barrier opening for clinical applications of neurodegenerative diseases.

  2024cites this paper
• Micro/nanoparticle-enabled ultrasound therapy of brain diseases

  2024cites this paper
• Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer’s disease models

  2024cites this paper
• Focused ultrasound assisted delivery of immunomodulating agents in brain cancer: A review.

  2024cites this paper
• The Role of Reactive Oxygen Species in Alzheimer's Disease: From Mechanism to Biomaterials Therapy

  2024cites this paper
• A comprehensive review of advanced focused ultrasound (FUS) microbubbles-mediated treatment of Alzheimer's disease

  2024cites this paper
• Cavitation monitoring, treatment strategy, and acoustic simulations of focused ultrasound blood-brain barrier disruption in patients with glioblastoma.

  2024cites this paper
• Multimodal beneficial effects of BNN27, a nerve growth factor synthetic mimetic, in the 5xFAD mouse model of Alzheimer’s disease

  2024cites this paper
• Focused Ultrasound-Mediated Delivery of Anti-Programmed Cell Death-Ligand 1 Antibody to the Brain of a Porcine Model

  2023cites this paper
• Engineering of Electrospun Nanofiber Scaffolds For Repairing Brain Injury

  2023cites this paper
• Transcranial low-intensity ultrasound stimulation for treating central nervous system disorders: A promising therapeutic application

  2023cites this paper
• Reconsidering the role of blood-brain barrier in Alzheimer’s disease: From delivery to target

  2023cites this paper
• Long-lasting restoration of memory function and hippocampal synaptic plasticity by focused ultrasound in Alzheimer's disease.

  2023cites this paper
• Preclinical Research on Focused Ultrasound-Mediated Blood–Brain Barrier Opening for Neurological Disorders: A Review

  2023cites this paper
• Research and progress of focused ultrasound in the treatment of Alzheimer’s disease

  2023cites this paper
• Moschus ameliorates glutamate-induced cellular damage by regulating autophagy and apoptosis pathway

  2023cites this paper
• Molecular mechanisms of Alzheimer's disease: From therapeutic targets to promising drugs

  2022cites this paper
• Blood-brain barrier leakage in Alzheimer's disease: From discovery to clinical relevance.

  2022cites this paper
• Role of Cholinergic Signaling in Alzheimer’s Disease

  2022cites this paper
• Neurotechnological Approaches to the Diagnosis and Treatment of Alzheimer’s Disease

  2022cites this paper
• Anti-Parkinsonian Therapy: Strategies for Crossing the Blood–Brain Barrier and Nano-Biological Effects of Nanomaterials

  2022cites this paper
• Alpha-Synuclein Targeting Therapeutics for Parkinson's Disease and Related Synucleinopathies

  2022cites this paper
• Understanding How Physical Exercise Improves Alzheimer’s Disease: Cholinergic and Monoaminergic Systems

  2022cites this paper
• Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses

  2022cites this paper
• Stable Cavitation Interferes with Aβ16-22 Oligomerization

  2022cites this paper
• Opportunities and challenges in delivering biologics for Alzheimer's disease by low-intensity ultrasound.

  2022cites this paper
• Nanomedicine and nanobiotechnology applications of magnetoelectric nanoparticles.

  2022cites this paper
• Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity

  2022cites this paper
• Xanomeline restores endogenous nicotinic acetylcholine receptor signaling in mouse prefrontal cortex

  2022cites this paper
• Applications of Focused Ultrasound-Mediated Blood-Brain Barrier Opening.

  2022cites this paper
• Rosmarinic acid potentiates and detoxifies tacrine in combination for Alzheimer's disease.

  2022cites this paper
• The therapeutic potential of nerve growth factor combined with blood-brain barrier modulation by focused ultrasound for neurodegenerative disorders

  2021cites this paper
• Ultrasound delivery of a TrkA agonist confers neuroprotection to Alzheimer-associated pathologies

  2021cites this paper
• Current Advances in Immunotherapy for Glioblastoma Multiforme and Future Prospects

  2021cites this paper
• The Applications of Focused Ultrasound (FUS) in Alzheimer’s Disease Treatment: A Systematic Review on Both Animal and Human Studies

  2021influential citation
• Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis

  2021cites this paper
• Multi-mechanical waves against Alzheimer’s disease pathology: a systematic review

  2021cites this paper
• A comparative study of the effects of Aducanumab and scanning ultrasound on amyloid plaques and behavior in the APP23 mouse model of Alzheimer disease

  2021cites this paper
• Circular RNA Cwc27 contributes to Alzheimer’s disease pathogenesis by repressing Pur-α activity

  2021cites this paper
• A Review of Techniques for Biodelivery of Nerve Growth Factor (NGF) to the Brain in Relation to Alzheimer's Disease.

  2021cites this paper
• Intravenous and Non-invasive Drug Delivery to the Mouse Basal ForebrainUsing MRI-guided Focused Ultrasound.

  2021cites this paper
• Nerve growth factor orchestrates NGAL and matrix metalloproteinases activity to promote colorectal cancer metastasis

  2021cites this paper
• Bushen-Huatan-Yizhi formula reduces spatial learning and memory challenges through inhibition of the GSK-3β/CREB pathway in AD-like model rats.

  2021cites this paper
• Applications of focused ultrasound in the brain: from thermoablation to drug delivery

  2020cites this paper
• Recent Advances on Ultrasound Contrast Agents for Blood-Brain Barrier Opening with Focused Ultrasound

  2020cites this paper
• The evolution of nerve growth factor inhibition in clinical medicine

  2020cites this paper
• Clinically approved IVIg delivered to the hippocampus with focused ultrasound promotes neurogenesis in a model of Alzheimer's disease.

  2020influential citation
• Radioligands for Tropomyosin Receptor Kinase (Trk) Positron Emission Tomography Imaging

  2019cites this paper
• Multimodal bene�cial effects of BNN27, a Nerve Growth Factor synthetic mimetic, in the 5xFAD mouse model of Alzheimer’s Disease

  year unknowncites this paper