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 (A3) assembly that we named A3*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 Alphabeta*56 in the human brain tissues and cerebrospinal fluid. We measured the prominence of several oligomers including Alphabeta*56 in three clinical groups: non-cognitively impaired age-matched normals (NCI), mild cognitive impairment (MCI) and Alzheimer's disease(AD). We found that Alphabeta*56 levels rise during the 5""""""""^ 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 A3*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 Alphabeta*56 combining in vitro and in vivo paradigms. Finally we plan to evaluate whether Alphabeta oligomers including Alphabeta*56 represent the A3 entity(ies) connecting the two phenotypic hallmarks ofthe disease, namely amyloid plaques and neurofibrillary tangles.
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.
|Sherman, Mathew A; LaCroix, Michael; Amar, Fatou et al. (2016) Soluble Conformers of AÎ² and Tau Alter Selective Proteins Governing Axonal Transport. J Neurosci 36:9647-58|
|Lesne, Sylvain E (2014) Toxic oligomer species of amyloid-Î² 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 AÎ² rescues cognitive and synaptic impairment in a mouse model of Alzheimer's disease. J Neurosci 34:7871-85|
|Larson, Megan E; Sherman, Mathew A; Greimel, Susan et al. (2012) Soluble Î±-synuclein is a novel modulator of Alzheimer's disease pathophysiology. J Neurosci 32:10253-66|
|Larson, Megan E; LesnÃ©, Sylvain E (2012) Soluble AÎ² 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 AÎ² with pathological tau changes in Alzheimer's disease. J Neurosci 32:16857-71a|