Alzheimer's disease (AD) is a progressive neurodegenerative dementia affliciting over 4 million people in the United States. There is no treatment and the disease inevitably causes derangement and death. AD has multiple etiologies, but in all cases a major pathological hallmark is the accumulation of amyloid beta protein (Abeta). Accumulated Abeta occurs in varius multimeric forms and in association with a variety of other molecules. Abeta also can accumulated in the absence of neurodengeneration of dementia, which suggests that its deposition is not a simple marker for extensive cell death. We propose to investigate the relation of Abeta to AD neuropathology in the context of the following working theory: When monomers of Abeta self-assemble into multimers, they form toxic ligand-like domains that alternatively can be exposed or cryptic, depending on the final multimeric structure. If the toxic domains cannot interact with neurons, the multimers are innocuous. If, on the other hand, the toxic domains do interact with neurons, themultimers are pathogenic and they play a role in the progressive neurodegeneration of Alzheimer's disease. The final multimeric structure is highly sensitive to conditions of assembly. Certain glial derived proteins assoicated with Alzheimer's pathology (such as ApoJ or butyrylcholinesterase) promote a particularly dangerous form of oligomeric Abeta that is both toxic and diffusible. These Abeta derived active ligands (ADALs) bind to nerve cell surfaces and corrupt vital neuronal signal transductionpathways, forcing nerve cell dysfunction and death. Preliminary data are presented that support each element of this working theory. Predictions of the theory will be tested using a series of characterized amyloid obtained from collaborations with Drs. Drafft and Van Eldik. Specific responses of nerve cell lines and brain slice cultures will be monitored using assay established here. Significant conclusions from these experiments will be tested for their relevance to neurodegenerationin Alzheimer's- afflicted brain tissue, in collaboration with Dr. Mesulam.
AIM 1 Determine how Abeta neurotoxicity is altered by experimentally controlled variations in its multimeric state; from experiments with cloned cell lines, data will compare the cytotoxicity of a series of amyloid made by mixing synthetic Abeta with AD-related glial derived proteins.
AIM2 Define a molecular signature for each particular amyloid and show whether common as well as unique elements exist in the response to neurodegenerative amyloids; data will compare cell line responses to the amyloids evaluated in AIM 1 via assays germane to mechanisms of neurodegeneration.
AIM 3 Test the pathogenic relevance of cell line responses to Ab; data will show if responses to Abeta amyloids seen in AIMs 1 and 2 are reproduced in mammalian brain tissue, and will show if evidence of such changes may exist in tissue from Alzheimer's-afflicted patients. Data will provide salient tests of the modified amyloid cascade hypothesis. New insight is expected into specific pathways that make neurons vulnerable to toxic insults and into factors that modulate the toxicity of Abeta. Hypothetically, the proposed impact of Abeta amyloids on signal tranduction could lead to severe, end-stage dementia via nerve cell death; at earlier stages, corrupted signaling could lead to memory failure and other cognitive impairments via degeneration of cytoskeletal-dependent synaptic plasticity. If the amyloid hypothesis ultimately should prove valid, this project will provide important models for identifying drug target candidates and testing neuroprotective agents.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Evanston Hospital
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