Research Project
7486263
DESCRIPTION (provided by applicant): The amyloid hypothesis is central to Alzheimer's disease research. Amyloid-beta plaques are a major neuropathological feature of Alzheimer's disease, although plaques distort neuronal morphology, the effects of the distortion on neuronal activity have only begun to be measured. In addition, amyloid-beta accumulation has been shown to affect cognitive function in transgenic mice. However, amyloid-beta accumulates in soluble and insoluble forms, and it is unclear how the different forms of the protein affect neuronal function. This study will measure the effects of soluble and insoluble amyloid-beta on neuronal properties in the intact neocortex of transgenic rodents with significant soluble amyloid-beta accumulation and plaque aggregation. Using in vivo intracellular recordings, functional properties of identified neocortical pyramidal neurons will be measured in the intact cortex and correlated with levels of soluble and insoluble amyloid-beta accumulation. Cellular properties, input-output relationships, and synaptic responses to electrical and sensory stimulation will be measured and the relationships to levels of amyloid-beta quantified. The sensory receptive fields of the cortical neurons will be mapped, and this will allow measurement of the functional effects of disruption of the neocortical connectivity by amyloid-beta plaque aggregation. Intrinsic neuronal properties and synaptic responses will be measured in transgenic mice with elevated soluble amyloid-beta prior to plaque deposition, and at a later age when significant plaque deposition has occurred. In addition, wild-type rodents will be infused with soluble, oligomeric amyloid-beta to directly test the effect of the protein on neuronal function. Finally, using anti-amyloid-beta antibody treatment to clear soluble amyloid-beta and plaques from the cortex, the degree of recovery of function will be measured. This study will provide a description of the effects of various forms of amyloid-a on intrinsic electrophysiological properties, synaptic responses, and sensory receptive fields of neocortical neurons in the intact network.
