This application concerns a new possibility for the role of Abeta in AD. It is designated to investigate the loss of synaptic plasticity and death of nerve cells caused by nonfibrillar Abeta oligomers. Oligomers accumulate in AD brain, and current best evidence indicates they contribute to disease progression, potentially accounting for the imperfect correlation with amyloid.
Aims focus on three key properties of oligomers (referred to as """"""""ADDLs,"""""""" for Abeta derived diffusable ligands). (i) ADDLs inhibits LTP in under an hour, one of the fastest known responses to any form of Abeta. (ii) ADDLs kill hippocampal neurons by a mechanism blocked by germline knockout of Fyn, a protein tyrosine kinase coupled to NMDA receptors and tetanus-induced LTP. (iii) ADDLs bind to cell surface proteins that are trypsin-sensitive and cluster at punctate """"""""hot spots."""""""" The goal is to understand the molecular basis for ADDL neurotoxicity. Two hypotheses will be evaluated. First, ADDLs may be small protein ligands that cause damage by disturbing Fyn signal transduction, a consequence mediated by specific toxin receptors. Alternatively, ADDLs may disrupt cell integrity with little or no specificity, generating a global breakdown of cell physiology that includes loss of LTP and culminates in cell death. Predictions of these hypotheses will be tested by the proposal's AIMs.
Aim 1. LTP or neurotransmission-Is the synaptic impact of ADDLs specific for LTP, or is synaptic function broadly impaired.
Aim 2. Types of plasticity-Do ADDLs affect multiple types of neuronal plasticity, or only tetanus induced LTP? Aim 3. Molecular impact-Does toxicity stem form ADDLs impact on Fyn, or do ADDLs attack at alternative and perhaps multiple sites? Aim 4. Cell surface reactions-Are ADDLs bound by specific """"""""toxin receptors,"""""""" or is ADDL activity not dependent on unique binding sites? Results from this application will give a new basis for understanding the actions of Abeta oligomers found in human brain. In a best-case outcome, findings would provide novel targets for therapies that ultimately could reverse and not just slow down AD memory impairment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG018877-03
Application #
6615732
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Snyder, Stephen D
Project Start
2001-08-01
Project End
2005-07-31
Budget Start
2003-08-01
Budget End
2005-07-31
Support Year
3
Fiscal Year
2003
Total Cost
$292,257
Indirect Cost
Name
Northwestern University at Chicago
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Lithner, Christina Unger; Lacor, Pascale N; Zhao, Wei-Qin et al. (2013) Disruption of neocortical histone H3 homeostasis by soluble A?: implications for Alzheimer's disease. Neurobiol Aging 34:2081-90
Bomfim, Theresa R; Forny-Germano, Leticia; Sathler, Luciana B et al. (2012) An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated A? oligomers. J Clin Invest 122:1339-53
Ferreira, Sergio T; Klein, William L (2011) The A? oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease. Neurobiol Learn Mem 96:529-43
Saraiva, Leonardo M; Seixas da Silva, Gisele S; Galina, Antonio et al. (2010) Amyloid-? triggers the release of neuronal hexokinase 1 from mitochondria. PLoS One 5:e15230
De Felice, Fernanda G; Vieira, Marcelo N N; Bomfim, Theresa R et al. (2009) Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A 106:1971-6
De Felice, Fernanda G; Wu, Diana; Lambert, Mary P et al. (2008) Alzheimer's disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging 29:1334-47
Zhao, Wei-Qin; De Felice, Fernanda G; Fernandez, Sara et al. (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J 22:246-60
De Felice, Fernanda G; Velasco, Pauline T; Lambert, Mary P et al. (2007) Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282:11590-601
Lambert, Mary P; Velasco, Pauline T; Chang, Lei et al. (2007) Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem 100:23-35
Lacor, Pascale N; Buniel, Maria C; Furlow, Paul W et al. (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci 27:796-807

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