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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG015501-02
Application #
6098814
Study Section
Project Start
1998-09-30
Project End
1999-08-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Evanston Hospital
Department
Type
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60201
Chromy, Brett A; Nowak, Richard J; Lambert, Mary P et al. (2003) Self-assembly of Abeta(1-42) into globular neurotoxins. Biochemistry 42:12749-60
Stine Jr, W Blaine; Dahlgren, Karie N; Krafft, Grant A et al. (2003) In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis. J Biol Chem 278:11612-22
Gong, Yuesong; Chang, Lei; Viola, Kirsten L et al. (2003) Alzheimer's disease-affected brain: presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci U S A 100:10417-22
Wang, Hai-Wei; Pasternak, Joseph F; Kuo, Helen et al. (2002) Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res 924:133-40
Van Eldik, Linda J; Koppal, Tanuja; Watterson, D Martin (2002) Barriers to Alzheimer disease drug discovery and development in academia. Alzheimer Dis Assoc Disord 16 Suppl 1:S18-28
Sheng, J G; Jones, R A; Zhou, X Q et al. (2001) Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation. Neurochem Int 39:341-8
Klein, W L; Krafft, G A; Finch, C E (2001) Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci 24:219-24
Guo, L; Sawkar, A; Zasadzki, M et al. (2001) Similar activation of glial cultures from different rat brain regions by neuroinflammatory stimuli and downregulation of the activation by a new class of small molecule ligands. Neurobiol Aging 22:975-81
Koppal, T; Lam, A G; Guo, L et al. (2001) S100B proteins that lack one or both cysteine residues can induce inflammatory responses in astrocytes and microglia. Neurochem Int 39:401-7
Peskind, E R; Griffin, W S; Akama, K T et al. (2001) Cerebrospinal fluid S100B is elevated in the earlier stages of Alzheimer's disease. Neurochem Int 39:409-13

Showing the most recent 10 out of 20 publications