Aβ-Induced Apoptosis in Cultured CNS Neurons

Alzheimer’s disease (AD) is a debilitating brain disease marked by often severe cognitive disorders. Existing evidence suggests that amyloid-beta (Aβ) peptides can cause or contribute to AD, but how they do so is not clear. A significant problem in this area is that Aβ peptides spontaneously aggregate to generate several distinct “assembly forms” that can differ in their biological properties. However, which form or forms cause AD is not known. This proposed research will test a two-part hypothesis: 1) Assembly forms of Aβ differ in their potency for inducing programmed cell death (apoptosis) in central nervous system neurons, and 2) a particular subtype of neurotransmitter receptor on such neurons mediates the triggering of cell death by Aβ. The Specific Aims will test each part of this hypothesis. Aim 1: Quantify and compare the ability of different Aβ assembly forms to induce apoptosis in cultured CNS neurons; Aim 2: Determine whether normal functioning of the receptor subtype in question is necessary for Aβ to induce apoptosis in CNS neurons. The completed work will set up subsequent studies to test treatments to prevent the apoptotic effects of Aβ, with the focus on directly interfering with Aβ binding to CNS neurons.