Cuello, A. Claudio G
Studies on the plasticity of CNS cholinergic neurons
Alzheimer's disease & other dementias
Our recent pharmacological studies revealed the existence of a group of enzymes in the brain responsible for the production and degradation of the protein Nerve Growth Factor (NGF). NGF is crucial for the “healthy” status of a group of neurons known as basal forebrain cholinergic neurons (BFCNs). These brain cells have key roles in learning and memory and are damaged in individuals with Alzheimer’s disease (AD). Previous investigations from our group showed that the NGF pathway is affected in AD brains, so that NGF fails to mature and breaks down more quickly. These changes mean that there are reduced levels of NGF to BFCNs and explains how their degeneration occurs in AD. The present grant renewal aims to investigate whether this pathway is responsible for the “well-being” of BFCNs that contact NGF releasing areas. We propose that alterations in the NGF metabolic pathway exist in any situation where amyloid-beta (Abeta) peptides build up, as they do in AD. To test this, we will explore the NGF metabolic pathway in our rat model of AD and in the brains of Down’s syndrome (DS) sufferers. These people have an extra chromosome containing the gene expressing the precursor protein for the formation of Abeta (the peptide fragment central to AD development). Most DS individuals accumulate Abeta and develop AD by mid-life. We also want to investigate if the inhibition of molecules which break down NGF can reverse the deficits seen in AD. In these studies we will use our rats which mimic AD memory deficits. We will conduct a pharmacological investigation to test if cholinergic degeneration worsens AD pathology and if the use of drugs which protect the brain can delay onset of AD. Our investigations are important as it is estimated that a delay of 5 years in disease onset could reduce the incidence of AD by half.