Behind Closed Doors: The Emerging Role of Focused Ultrasound in Alzheimer’s Disease Justin Mendoza
Alzheimer’s Disease (AD) has become recognized as a neurodegenerative condition in which declination in cognitive function progressively worsens over time. Hallmarks of AD include basal forebrain cholinergic neuron (BFCN) dysfunction, leading to the loss of post-synaptic connections associated with memory functioning. Another known defect that has been correlated with the early onset of this particular condition is the aberrant decline in the levels of nerve growth factor (NGF), a selective neurotrophin that propagates survival of mature neurons, once bound to its cognate receptor, tropomyosin-related kinase A (TrkA). The NGF-mediated TrkA pathway has been elucidated to support survival mechanisms, as well as the mediation of apoptotic signaling, depending on the bound ligand. With the available information of the pathophysiology and intracellular mechanisms of AD, current research aims to mitigate the severity of early hallmarks; however, a major limitation that prevents the delivery and efficacy of therapeutic regimens is the tightly regulated barrier that is the blood-brain barrier (BBB). As a result, current research has adapted to this limitation, proposing the use of non-invasive methods, such as magnetic resonance imaging-guided focused ultrasound (MRIgFUS) to increase the permeability of the BBB, as a means to deliver therapeutic compounds to elicit the TrkA cascade pathway. Through the work of Xhima et al., the TrkA agonist known as D3, had rescued cholinergic functioning within AD murine models, as opposed to monotherapy involving NGF alone, using MRIgFUS to deliver the agonist. As a result, the use of protective neurotrophins, along with the use of MRIgFUS to circumvent the BBB holds promising results, which can be used to further clinical trials in AD patients. Further research is warranted to elucidate the mechanisms of NGF-mediated therapy, as NGF alone is unable to stimulate TrkA-dependent signaling in an AD murine model. Key words: Alzheimer’s disease, nerve growth factor, blood-brain barrier, magnetic resonance imagingguided focused ultrasound, TrkA, D3
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