Grant: Operating Grant

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a gradual loss of memory followed by deterioration of higher cognitive functions such as language, calculation and judgment. The neuropathological features associated with AD include abnormal extracellular deposits of amyloid beta (Ab) peptide in neuritic plaques, intracellular accumulation of filamentous structures termed neurofibrillary tangles and loss of neurons (nerve cells) in selected regions of the brain. Accumulated evidence indicates that deposition of Ab peptides may trigger the loss of neurons and subsequent development of AD pathology. Among vulnerable neurons, the basal forebrain neurons which use acetylcholine (ACh) as a neurotransmitter (chemical messenger) and play an important role in learning and memory processing are known to be most severely affected in the AD brain. However, very little is known about why these neurons are preferentially vulnerable in AD pathology. We have earlier reported that short-term exposure of rat brain slices to Ab peptides can markedly inhibit ACh release from the hippocampus and cortex - the regions which receive inputs from the forebrain cholinergic neurons, whereas long-term exposure to the peptides can lead to the loss of cultured forebrain cholinergic neurons. However, the cellular mechanisms by which Ab peptide can cause the inhibition of ACh release or the loss of forebrain cholinergic neurons remain unclear. To address this issue our laboratory is currently investigating how various Ab-related peptides can mediate their effects on the basal forebrain cholinergic neurons in normal rat brain as well as in mice that have been genetically modified to produce excess Ab peptides. This study will determine the underlying basis of functional interrelationships between Ab peptides and brain cholinergic system and will define whether inhibition of Ab production can prevent the onset and/or retard the progression of AD.