Alzheimer's disease (AD) is characterized by three major pathological findings, the abnormal accumulation of A? in the form of senile plaques, the presence of neurofibrillary tangles (NFTs) and the existence of substantial cell loss and dysfunction in certain brain regions. While there has been tremendous efforts invested in the identification of compounds that can influence A? levels and NFT formation, very little effort has been directed towards potential cell replacement strategies for Alzheimer's disease. The identification of ongoing neurogenesis in the adult mammalian CNS presents the intriguing possibility of utilizing progenitor cells as a novel source for cell replacement strategies for diseases such as AD. In theory, this could potentially be accomplished either by introducing exogenous progenitor cells into the CNS or by stimulating the production and maturation of endogenous progenitor cells. The possibility of stimulating endogenous progenitor cells to divide and take on a mature, functional phenotype is particularly intriguing as this approach is likely to have several advantages over transplant strategies, especially with respect to potential long term functional improvement. Recently, we have demonstrated that chronic exposure to certain dopamine receptor agonists can cause a significant increase in endogenous neurogenesis in a rat model of Parkinson's disease (PD). Following chronic infusion of 7-OH-DPAT (a dopamine D3 selective receptor agonist), we observed a near-complete reversal of the motor defects characteristic of this animal model of PD. Importantly, these effects persisted long after drug washout, clearly indicating a change in underlying pathology in this model. Neuropathological assessment revealed the degree and time course of this behavioral recovery coincided directly with an increase in histological staining for dopaminergic neurons in the SNC and an increase in retrograde labeling of nigrostriatal projections. Collectively, these data indicate that chronic agonist treatment can, at least partially, restore functional and anatomical markers of nigrostriatal integrity through an increase in dopaminergic neurogenesis. In Alzheimer's disease, one of the earliest characteristic pathological features is a substantial loss of cholinergic neurons in the basal forebrain, the major source of cholinergic innervation to the hippocampus. The cholinergic system of the basal forebrain is one of the key transmitter systems involved in learning and memory and reductions in cholinergic innervation likely underlie many of the early cognitive deficits associated with AD. In fact, virtually all of the FDA approved drugs to treat AD rely on attempting to increase this cholinergic transmission by blocking a key enzyme, acetylcholinesterase. The efficacy of the drugs is limited, however, and when the cells eventually die the drugs are no longer effective. What if, however, we were able to repopulate these cells? This is the fundamental question that we seek to address in this proposal. We rationalized that the findings we observed with chronic exposure to dopamine D3 receptor stimulation in a PD model may also be translatable to other neuronal types, provided an appropriate agonist can be identified. To test this hypothesis for cholinergic neurons, we treated animals for several weeks with various cholinergic agonists, including both nicotinic as well as muscarinic receptor agonists. Early preliminary data indicate that muscarinic agonists do indeed increase cytogenesis in a manner very similar to that initially observed with D3 agonist treatment in a PD model. Thus, we now propose to determine whether or not this increase in cytogenesis will result in an increase in cholinergic neurons and whether or not this increase may translate to neuronal recovery and improved cognition in a rodent model of AD.
Lay Summary Alzheimer's disease is a devastating illness involving the loss of cells in a select regions of the brain. In this application, we seek to determine whether pharmacological intervention can stimulate remaining cells to regenerate and take the place of these lost cells. If successful, these studies may yield novel insights into potential treatment strategies and will also increase our understanding of the factors capable of regulating new cell formation in the adult brain.
| Van Kampen, Jackalina M; Eckman, Christopher B (2010) Agonist-induced restoration of hippocampal neurogenesis and cognitive improvement in a model of cholinergic denervation. Neuropharmacology 58:921-9 |
