Molecular and morphological analyses of basal forebrain cholinergic neurons in mouse models of aging and Alzheimer's disease

• Main Author: Norman, Timothy Alfred Jr.
• Language: en_US
• Published: Boston University 2015
• Online Access: https://hdl.handle.net/2144/12173

Thesis (M.A.)--Boston University === Basal forebrain cholinergic neurons (BFCNs) of the medial septal nuclei, the diagonal bands of Broca and the nucleus basalis magnocellularis synthesize acetylcholine (ACh) and their projections extend to the cerebral cortex, hippocampus and the amygdala. ACh neurotransmission is essential for learning, attention, memory, arousal and sleep. BFCNs are dependent on a regulated neurochemical environment for the induction, development, maturation and maintenance of their phenotype and viability. However, events that compromise this neurochemical environment can contribute to BFCN dysfunction and/or degeneration, decreased ACh levels and disrupted brain function. During normal aging and Alzheimer’s disease (AD) BFCNs become more vulnerable to dysfunction due to trophic factor withdrawal, cell signaling impairments and other cytopathologic changes. AD is characterized by the deposition of Amyloid-beta (Aβ) plaques and neurofibrillary Tau tangles (NFTs) in the cortex and hippocampus. These pathological AD hallmarks overlap with cortical and hippocampal cholinergic dysfunction, implicating both as the drivers of cognitive and behavioral decline associated with AD. Since, BFCNs are highly vulnerable to AD pathophysiology, factors that support the BFCN phenotype may have practical use in preserving neuronal networks and cognitive function. There is now strong evidence that bone morphogenetic protein-9 (BMP9 also known as growth/differentiating factor 2, GDF2) acts as an induction and maintenance factor that regulates BFCN differentiation in-vitro and in-vivo. Here we used transgenic mice that express green fluorescent protein (GFP) in BFCNs to make observations concerning the BFCN phenotype in aging and AD. We found qualitative evidence that BFCNs of the 24-month old WT/ChAT-GFP mice were smaller and more rounded with shorter processes when compared to 6- month old mouse BFCNs. We analyzed the effects of intracerebroventricular infusion of BMP9 on BFCN projection fibers in the APPswe/PS1dE9 mouse model of AD using laser scanning confocal microscopy. BMP9 not only increased the density of cholinergic projection fibers in the hippocampus of wild type and AD model APPswe/PS1dE9 mice, but it also reduced the plaque burden in the hippocampus of the AD mouse model. These data indicate that BMP9 ameliorated two major pathophysiologic hallmarks of AD, observable in these transgenic APPswe/PS1dE9 mice. BMP9 reduced Aβ plaque burden in this AD model, and enhanced the outgrowth and viability of cholinergic fibers within the hippocampus of both wild-type and APPswe/PS1dE9 mice. [TRUNCATED]