THE THERAPEUTIC POTENTIAL OF DEEP BRAIN STIMULATION AS A TREATMENT FOR ALZHEIMER’S DISEASE

Abstract

Deep brain stimulation of the cholinergic forebrain and its effects on memory and neurotrophic and beta-amyloidogenic markers in an Alzheimer’s mouse The cholinergic forebrain or nucleus basalis of Meynert (nbM) provides acetylcholine to the entire cortical mantle and degenerates sooner than other brain regions during Alzheimer’s disease (AD). The current frontline AD therapy of cholinesterase inhibitors improves cognition for about half of a year until becoming ineffective and often associates with peripheral cholinergic side effects. Our previous research demonstrated that intermittent, instead of continuous, electrical stimulation of the nbM improves memory in an adult primate model. Here we implanted bilateral electrodes into the nbM of 4-month-old wild-type and 5xFAD mice. They received 1-hr of daily nbM intermittent stimulation at 100uA until the age of 9 months. Stimulation enhanced visuospatial memory when learning the Morris water maze task. However, only nbM-stimulated 5xFAD mice demonstrated significantly enhanced performance of the probe test. In both genetic backgrounds, treatment increased expression of the ligand mNGF as well as the neurotrophic tyrosine receptor kinases TrkA and TrkB receptors. Stimulation also reduced expression of the amyloidogenic enzyme beta-site APP cleaving enzyme 1 (BACE1), as well as displayed reduction in Aβ42 concentration. To determine the necessity of the various subtypes of cholinergic receptors, we administered non-selective and selective cholinergic antagonists in adjunct with stimulation to see which receptor subtypes were necessary in altering the investigated biomarkers. A conditional knockout of 7-nicotinic acetylcholine receptors further supported the pharmacology study that concluded the necessity of this specific receptor in the elicitation of the stimulation response.