EXPANSION OF ENDOGENOUS ADULT NEURAL PRECURSOR CELL POPULATIONS TO ACHIEVE NEURONAL REPLACEMENT AND FUNCTIONAL RECOVERY IN ALZHEIMER-LIKE CHOLINERGIC DEGENERATION

Alzheimer disease is a devastating neurological disorders that leads to progressive loss of cognition and memory, and accounts for the majority of dementia in people over 65 years of age. One characteristic feature of Alzheimer disease is the degeneration of neurons that release acetylcholine (cholinergic cells) and that provide a rich innervation of the cerebral cortex and hippocampus. It is known that death of these neurons plays a fundamental role in cognitive decline of Alzheimer's disease patients. In this research proposal we plan to develop a strategy for replacing these dead neurons through the stimulation of the endogenous neural stem cells. Indeed, it is known that the adult brain contains neural stem cells (cells that can self-renew themselves as well as make new neurons) in the region surrounding the cerebral ventricles. It is also known that the administration of trophic factors, such as BDNF, into the cerebral ventricles of adult rodents can stimulate these stem cells to proliferate and make new neuronal cells that migrate out into the adult brain. We will induce pharmacologically the death of cholinergic cells in adult rats and we will treat these animals with BDNF. We will assess at an anatomical level whether the new neurons generated from endogenous stem cells can replace the lost cholinergic neurons. Using learning and memory tasks, we will also ask if the new cells can produce recovery of cognitive functions in these animals.