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
Sherman, Mathew A; LaCroix, Michael; Amar, Fatou et al. (2016) Soluble Conformers of A? and Tau Alter Selective Proteins Governing Axonal Transport. J Neurosci 36:9647-58
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
Larson, Megan E; Lesné, Sylvain E (2012) Soluble A? oligomer production and toxicity. J Neurochem 120 Suppl 1:125-39
Larson, Megan; Sherman, Mathew A; Amar, Fatou et al. (2012) The complex PrP(c)-Fyn couples human oligomeric A? with pathological tau changes in Alzheimer's disease. J Neurosci 32:16857-71a
Larson, Megan E; Sherman, Mathew A; Greimel, Susan et al. (2012) Soluble ?-synuclein is a novel modulator of Alzheimer's disease pathophysiology. J Neurosci 32:10253-66
Sherman, Mathew A; Lesné, Sylvain E (2011) Detecting a?*56 oligomers in brain tissues. Methods Mol Biol 670:45-56