The broad long-term objective of this proposal is to understand how memory loss occurs in Alzheimer's disease (AD). In 2006, we have shown that a specific amyloid beta (AB) assembly that we named AB*56 was likely the cause of cognitive decline in the mouse model of AD, Tg2576. As part of the mentored phase of this award (K99), we confirmed the existence of AB*56 in the human brain tissues and cerebrospinal fluid. We measured the prominence of several oligomers including AB*56 in three clinical groups: non-cognitively impaired age-matched normals (NCI), mild cognitive impairment (MCI) and Alzheimer's disease(AD). We found that AB*56 levels rise during the 5th decade of life during which the first signs of memory decline is noticeable (also known as AAMI) and its levels decrease with disease progression. Trimers peaked in MCI brain tissues while dimers slowly increased with dementia. In addition, we identified a putative receptor for AB*56. both in tissues from transgenic animals as well as in human brains. With this application, we propose to decipher the mechanism of action of AB*56 combining in vitro and in vivo paradigms. Finally we plan to evaluate whether AB oligomers including AB*56 represent the AB entity(ies) connecting the two phenotypic hallmarks of the disease, namely amyloid plaques and neurofibrillary tangles.

Public Health Relevance

If completed this proposal could provide novel targets for slowing down or preventing Alzheimer's disease based on the observation that multiple oligomers may be altering neuronal function at different stages ofthe disease (during the asymptomatic and symptomatic phases of AD, i.e. MCI and AD). Since alphabeta*56 rises first with ageing in humans, it represents an ideal candidate molecule to study in the context of AD prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Transition Award (R00)
Project #
5R00AG031293-03
Application #
8144811
Study Section
Special Emphasis Panel (NSS)
Program Officer
Refolo, Lorenzo
Project Start
2008-08-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$230,717
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Neurology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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