Aging is the biggest risk factor for the development of Alzheimer's disease (AD). Age-related degeneration of basal forebrain cholinergic neurons and accumulation of amyloid beta (A?) are greatly accelerated in AD, contributing to cognitive decline. Recent data suggests a critical bidirectional relationship between cholinergic dysfunction and A? toxicity. Cholinergic neurons are exquisitely sensitive to the toxic effects of A?, while deficits in muscarinic receptor (mAChR) function, particularly M1 and M3 receptors, leads to increased amyloidogenic processing of amyloid precursor protein (APP). However, despite obvious interactions between A? and the cholinergic system, a mechanistic understanding regarding their precise interactions is far from clear. Importantly, M1 mAChR agonists administered in vivo decrease A? in cerebral spinal fluid of AD patients and in AD mouse models, highlighting the importance of maintaining M1 receptor function in aging and in AD. In rodent models, cholinergic degeneration stimulates a remarkable neuronal rearrangement where noradrenergic sympathetic fibers from the superior cervical ganglia sprout into denervated regions of hippocampus and cortex. Importantly, sympathetic sprouting has been demonstrated in hippocampus of AD patients and confirmed by us in preliminary studies. During the last funding cycle, we discovered sprouting of """"""""new"""""""" cholinergic fibers in hippocampus that are completely dependent upon sprouting of sympathetic noradrenergic fibers from the SCG. The appearance of these new fibers correlates with the rescue of a M1 receptor dependent LTD at CA3-CA1 synapses. This finding indicates that an endogenous """"""""repair"""""""" mechanism is in place to maintain M1 receptor function and synaptic plasticity during age- and disease-related cholinergic degeneration. This discovery could offer an explanation for conflicting animal studies assessing the impact of cholinergic degeneration on hippocampal dependent learning and memory. Moreover, this cholinergic reinnervation could be responsible for the increase in cholinergic activity observed in AD patients in early stages of the disease. In this competitive renewal, we will use a multifaceted approach including behavioral assays, brain slice electrophysiology, biochemistry, immunohistochemistry and confocal imaging to address the following novel questions: Does hippocampal sympathetic sprouting and accompanying cholinergic reinnervation rescue hippocampal dependent learning and memory deficits induced by cholinergic denervation? Are the """"""""new"""""""" cholinergic fibers functional and do they cause the rescue of M1 mAChR function, mLTD, and learning? Does A? accumulation in animals with cholinergic degeneration directly interfere with mAChR signaling, mLTD induction/expression, and sympathetic sprouting? The results of these studies are expected to confirm a beneficial role of sympathetic sprouting in maintaining hippocampal function during cholinergic degeneration, thus providing a novel therapeutic target for the treatment of cognitive decline in aging and in AD.
This study uses an animal model of cholinergic degeneration to investigate the impact of an endogenously stimulated repair mechanism on hippocampal dependent learning and synaptic plasticity. We anticipate that the results from this study will lead to the development of novel therapeutic targets for the treatment of age and disease related memory loss.
