Learning and memory are especially vulnerable and sensitive to Azheimer's disease (AD) and other agerelated dementias. Neurons in the hippocampus play a central role in many aspects of cognition involved in acquiring and recalling memories. Hippocampal neurons are also one of the first groups of neurons to show signs of incipient degradation during the course AD, sometimes preceding overt clinical symptoms. The hippocampus is comprised of several anatomically distinct regions that integrate information from multiple brain regions, but each hippocampal neuron also integrates information across its own dendritic domains. Though the principles and mechanisms of dendritic integration are still being determined, they are most wellunderstood in hippocampal CA1 pyramidal neurons, which show some of the earliest signs of degradation in AD. This proposal will use a combination of electron microscopy and whole-cell patch-clamp physiology in transgenic mice that overproduce toxic species of the amyloid beta protein and their non-transgenic littermate controls to identify which synapses are most sensitive to AD-like biochemical processing. Specifically, this proposal will use neuroanatomical tracing, unbiased quantitative electron microscopy, and immunogold electron microscopy for synaptic receptors to determine whether synapses are disassembled as a consequence of exposure to abnormally high levels of the amyloid-beta protein, and whether this disassembly follows a distance-dependent gradient throughout the hippocampal CA1 region as well as within individual hippocampal CA1 pyramidal neurons. The functional impact of amyloid beta overproduction on dendritic integration and synaptic plasticity will be determined by using somatic and dendritic whole-cell patch-clamp recordings from CA1 pyramidal neurons from both groups of mice. Taken together, the results of the proposed project will provide high-resolution insight into the cellular substrates underlying the synaptopathology of AD. Such insight, including the identification of synapses most vulnerable to AD, where they are on the neuron, and what their expression profile for several important signaling molecules is, will enhance our understanding of, and ultimately our ability to treat patients with, AD.
Patients with Alzheimer's disease and other age-related dementias exhibit marked impairments in acquiring and recalling memories. This project will use a combination of electron microscopy and whole-cell patchclamp physiology of hippocampal neurons to identify the synapses and dendritic regions most vulnerable to the devastating effects of Alzheimer's disease, with the ultimate goal of preventing or ameliorating them.
