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

Kristiana Xhima | Zendy; Kelly Markham-Coultes | Zendy; H. Nedev | Zendy; Stefan Heinen | Zendy; H. Uri Saragovi | Zendy; Kullervo Hynynen | Zendy; Isabelle Aubert | Zendy

Open Access

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

Author(s) -

Kristiana Xhima,

Kelly Markham-Coultes,

H. Nedev,

Stefan Heinen,

H. Uri Saragovi,

Kullervo Hynynen,

Isabelle Aubert

Publication year - 2020

Publication title -

science advances

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.928

H-Index - 146

ISSN - 2375-2548

DOI - 10.1126/sciadv.aax6646

Subject(s) - cholinergic , agonist , disease , function (biology) , neuroscience , cholinergic system , medicine , tropomyosin receptor kinase a , microbiology and biotechnology , biology , receptor , nerve growth factor

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 p75 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 p75, 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.

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