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

Authors: Xhima K, Markham-Coultes K, Nedev H, Heinen S, Saragovi HU, Hynynen K, Aubert I

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<sup>NTR</sup> 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<sup>NTR</sup>, 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.

Introduction

Purpose Drug delivery with BBB opening

Study Objective To determine whether MRI-guided focused ultrasound delivery of a selective TrkA agonist (D3) to the basal forebrain can restore cholinergic signaling and function in a mouse model of Alzheimer's disease.

Animal model / Human subject mouse, TgCRND8, 6 months, female

Disease model Alzheimer's disease

MRI or image guidance method stereotactic coordinates

Targeted brain region(s) Basal Forebrain

Cargo name and characteristics D3 (TrkA agonist)

Route of administration intravenous

Outcomes and Safety

Summary of Outcomes MRIgFUS-mediated BBB opening delivered the TrkA agonist D3 to the basal forebrain, restoring cholinergic signaling (pTrkA, pAkt) and acetylcholine release in AD mice.

Duration of biological effect 3 days

Safety-related matter The procedure was safe with no evidence of erythrocyte extravasation or neuronal apoptosis (Caspase-3/TUNEL negative); real-time subharmonic feedback minimized tissue damage.

Brain Region

Ultrasound Parameters

Ultrasound instrument preclinical MRI-guided focused ultrasound system (RK-100, FUS Instruments)

FUS Frequency 1.68 MHz

FUS Intensity not reported

FUS Pressure 1.25 MPa

FUS Mode not reported

Pulse duration 10 ms

Duration of a single FUS session 120 s

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