EFFECTS OF SELECTIVE STIMULATION OF MEDIAL SEPTAL CHOLINERGIC NEURONS ON ALZHEIMER’S DISEASE PATHOLOGY IN A TRANSGENIC MOUSE MODEL

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline. According to the cholinergic hypothesis, degeneration of basal forebrain cholinergic neurons and impaired cholinergic neurotransmission contribute significantly to disease pathogenesis. Medial septal cholinergic neurons provide extensive projections to multiple hippocampal subregions and critically regulate hippocampal network activity and memory-related processes. To enable selective manipulation of cholinergic neurons, we generated a 3xTg-AD–ChAT-Cre transgenic mouse line.
Aim: we investigated whether selective pharmacogenetic activation of medial septal cholinergic neurons influences AD-related pathological markers in the hippocampus.
Methods: Eight-month-old female 3xTg-AD–ChAT-Cre mice received stereotaxic injections of a Cre-dependent excitatory DREADD virus (pAAV-hSyn-DIO-rM3D(Gs)-mCherry) into the medial septum. Following a one-month recovery period, animals were treated for 10 consecutive days with intraperitoneal vehicle or clozapine-N-oxide (CNO). On day 12 animals were perfused two hours after the intraperitoneal injection. Immunohistochemistry was performed to assess mCherry, c-Fos and choline acetyltransferase (ChAT) expression and colocalization in the medial septum, as well as β-amyloid and phosphorylated tau (p-tau) immunoreactivity in the hippocampus.
Results: No prominent behavioral alterations were observed during the treatment period. Immunohistochemical analyses confirmed the appearance of mCherry in septal cholinergic cells and their activation after CNO injection. There was a tendency for reduced amyloid burden and hyperphosphorylated Tau concentration in the hippocampus after repeated cholinergic stimulation.
Conclusion: This study demonstrates the feasibility of selective pharmacogenetic modulation of medial septal cholinergic neurons in a transgenic AD model and provides a framework for exploring cholinergic contributions to hippocampal pathology.