Grant: Operating Grant

Alzheimer's disease is associated with the damage of a particular type of brain cell, the neuron. A specialized part of the neuron, termed the axon, is primarily and most severely affected by the toxicity of amyloid beta, present in the Alzheimer brain. It is well established that the degeneration of cholinergic neurons is significant in Alzheimer's disease and that it is related to learning and memory deficits. Enhancing cholinergic neurotransmission has been a main therapeutic focus with the use of acetylcholinesterase inhibitors, to prolong the action of the neurotransmitter acetylcholine. However, through the course of the disease, cholinergic axonal degeneration progresses and cholinergic cell bodies, deprived of nutrients such as nerve growth factor (NGF), ultimately die. Once such severe cholinergic degeneration occurs, treatments with acetylcholinesterase inhibitors have limited hope of success. The levels of acetylcholine, which could be protected by acetylcholinesterase inhibitors, are insufficient. Our goal is to develop a multi-component therapeutic strategy that will restore cognitive function by halting the toxicity of amyloid-beta using novel and effective methods including immunotherapy combined with non-invasive MRI-guided focused ultrasound delivery, scyllo-inositol, and rescuing cholinergic neurons by delivering NGF to specific areas of the brain. We hypothesize that limiting the toxicity of amyloid-beta will enhance the regenerative potential of cholinergic neurons in presence of NGF. In mouse models of Alzheimer's disease, this combined treatment is expected to restore axonal networks leading to the recovery of behavioral functions. The proposed research provides an improved basis for current and novel therapeutic interventions by reducing amyloid deposition and promoting neuronal regeneration to ameliorate cognitive function, and eventually to improve the quality of life for Alzheimer's patients.