Grant: Operating Grant - Priority Announcement: Aging (Bridge Funding)

Alzheimer's disease (AD), the most common type of senile dementia, is a progressive neurodegenerative disorder. Evidence indicates that extra- or intracellular accumulation of beta-amyloid (Ab) peptides may initiate the development of AD. The basal forebrain neurons which provide the major cholinergic input to the hippocampus and neocortex, areas involved in learning and memory processing, are most severely affected in the AD brain. To date, very little is known regarding the cause of the preferential vulnerability of these neurons and their association to Ab peptides. We have reported that exogenous Ab, under acute conditions, can inhibit acetylcholine (ACh) release from the hippocampus and cortex, whereas prolonged exposure to the peptide can lead to the degeneration of rat septal cultured cholinergic neurons. However, the cellular mechanisms by which Ab affects ACh release and/or survival of cholinergic neurons remain unclear. Recently, some studies have indicated that intracellular Ab peptide can play a critical role in the degeneration of neurons - thus raising an intriguing possibility that exogenous Ab peptides may trigger degeneration of cholinergic neurons by increasing the levels of intracellular Ab peptide. We are currently investigating how extracellular Ab peptide can regulate intracellular Ab levels and their role in mediating the effects on cholinergic neurons in normal rat brain as well as in transgenic mice overexpressing Ab peptide. This study will provide the underlying basis of functional interrelationships between Ab peptides and central cholinergic system and will define whether inhibition of Ab production can prevent the onset and/or retard the progression of AD.