Focused ultrasound delivery of a selective TrkA agonist rescues cholinergic function in a mouse model of Alzheimer's disease.
Kristiana XhimaK Markham-CoultesH NedevStefan HeinenH U SaragoviK HynynenIsabelle AubertPublished in: Science advances (2020)
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.
Keyphrases
- blood brain barrier
- growth factor
- cerebral ischemia
- mouse model
- clinical trial
- end stage renal disease
- stem cells
- cognitive decline
- machine learning
- chronic kidney disease
- mesenchymal stem cells
- ejection fraction
- newly diagnosed
- peritoneal dialysis
- magnetic resonance imaging
- prognostic factors
- cell therapy
- endothelial cells
- type diabetes
- cancer therapy
- spinal cord
- deep learning
- brain injury
- metabolic syndrome
- mild cognitive impairment
- computed tomography
- tissue engineering
- phase ii
- patient reported
- climate change