The long-term goal of this project is to further our understanding of the underlying mechanisms leading to memory loss in Alzheimer's disease (AD). In this study, we propose to investigate the composition and mechanisms of action of beta-amyloid (A?) assemblies disrupting learning and memory in mice and humans. We have previously demonstrated strong associations between A?*56, an endogenously formed 56-kDa A? assembly, and memory dysfunction in the Tg2576 APP transgenic mouse line and shown that purified A?*56 disrupts cognitive function when injected into the lateral ventricles of young, healthy rats. Unpublished data revealed that A?*56 physically interacts with NMDA receptor (NMDAR) complexes and evokes Ca2+ transients in primary neuronal cultures. In addition, we have detected multiple A? oligomers including A?*56 in humans at stages preceding clinical AD (i.e. pathological aging and mild cognitive impairment, MCI). Together, these observations have led us to propose that Alzheimer's disease begins as a disorder of synaptic function, triggered when A?*56 disrupts NMDAR-mediated synaptic physiology. In parallel other A? oligomers (dimers, trimers and A?-derived diffusible ligands, ADDLs) have displayed specific synaptotoxic and/or cytotoxic effects. Of recent focus, A? dimers were found in close association with amyloid plaques and are among the leading culprits mediating the neurotoxicity observed within the microenvironment of deposited amyloid, which has been proposed to underlie some aspects of dementia in AD. The diversity of these A?-induced effects suggests that multiple oligomeric A? species trigger specific mechanisms at different stages of the disease. Efforts to clarify this complex situation may reconcile disputes and resolve confusion concerning the relevance and significance of low-n versus high-n oligomers. The goal of the proposed study is to better understand the roles of distinct A? oligomers in the pathogenesis and progression of AD. To test this hypothesis, four aims are proposed: 1) determine whether specific A? oligomers are correlated with clinical status or cognitive decline in humans;2) identify molecular targets of specific A? oligomers;3) determine whether and how A? oligomers modulate NMDARs function in vitro;4) examine how A? oligomers affect NMDAR-dependent LTP in vivo.

Public Health Relevance

Understanding the mechanisms by which A? oligomers impair memory function is important for preventing AD, an ominous public health menace. Isolating and characterizing A? oligomers in humans may facilitate early diagnosis and prevention of AD. Determining how multiple A? oligomers trigger mechanisms at different stages of the disease may not only provide therapeutic targets for AD but also address why AD affects specific neural circuits in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033249-18
Application #
8286314
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
1994-08-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
18
Fiscal Year
2012
Total Cost
$520,403
Indirect Cost
$173,285
Name
University of Minnesota Twin Cities
Department
Neurology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Lesne, Sylvain E (2014) Toxic oligomer species of amyloid-? in Alzheimer's disease, a timing issue. Swiss Med Wkly 144:w14021
Fowler, Stephanie W; Chiang, Angie C A; Savjani, Ricky R et al. (2014) Genetic modulation of soluble A? rescues cognitive and synaptic impairment in a mouse model of Alzheimer's disease. J Neurosci 34:7871-85
Ashe, Karen H; Aguzzi, Adriano (2013) Prions, prionoids and pathogenic proteins in Alzheimer disease. Prion 7:55-9
Lesne, Sylvain E; Sherman, Mathew A; Grant, Marianne et al. (2013) Brain amyloid-* oligomers in ageing and Alzheimer's disease. Brain 136:1383-98
Handoko, Maureen; Grant, Marianne; Kuskowski, Michael et al. (2013) Correlation of specific amyloid-? oligomers with tau in cerebrospinal fluid from cognitively normal older adults. JAMA Neurol 70:594-9
Liu, Peng; Kemper, Lisa J; Wang, Jun et al. (2011) Grape seed polyphenolic extract specifically decreases a**56 in the brains of Tg2576 mice. J Alzheimers Dis 26:657-66
Reed, Miranda N; Liu, Peng; Kotilinek, Linda A et al. (2010) Effect size of reference memory deficits in the Morris water maze in Tg2576 mice. Behav Brain Res 212:115-20
Ashe, Karen H; Zahs, Kathleen R (2010) Probing the biology of Alzheimer's disease in mice. Neuron 66:631-45
Poling, Alan; Morgan-Paisley, Kineta; Panos, John J et al. (2008) Oligomers of the amyloid-beta protein disrupt working memory: confirmation with two behavioral procedures. Behav Brain Res 193:230-4
Lesne, S; Kotilinek, L; Ashe, K H (2008) Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function. Neuroscience 151:745-9

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