Alzheimer's disease (AD) is the major cause of dementia and one of the most disabling and burdensome health conditions worldwide. Currently there is an urgent need for new compound development for AD. Recent studies support that the accumulation of neurotoxic oligomeric aggregates made of the amyloid-beta protein (Ab) is a central event in the pathogenesis of AD. Recently, small molecule compounds that neutralize the neurotoxic effect of Ab oligomers (AbO) have shown promises in several studies. We have taken a new approach employing combinatorial chemistry and high throughput screening methods to discover cell-permeable, AbO-binding small molecule ligands that block AbO toxicity within both extracellular and intraneuronal sites. We hypothesize that these AbO ligands would interact with AbO to mask their epitopes that interact with cell targets, to prevent or reverse the aggregation of Ab peptides, and to reduce the level of AbO. These effects would provide neuroprotection from AD-like abnormalities in AD mouse models. Toward these ends, we have identified from screening several combinatorial libraries a promising compounds named LRL22. In this proposal, we plan to further optimize LRL22 using the """"""""one-bead one-compound (OBOC)"""""""" combinatorial library method (Aim 1). Using this method, thousands to millions of compounds can be easily generated and screened concurrently. We will synthesize OBOC libraries based on the building blocks of LRL22 and select compounds that bind AbO by screening using the ultra high throughput on-bead binding assay. The selected AbO ligands will be further screened for their cell protective effect using our high throughput cell-based AbO toxicity assays.
In Aim 2, we will determine the binding kinetics of selected AbO ligands, and will determine whether the binding results in interference with the AbO's interaction with synapses, or the reversal of Ab aggregation. Both are desirable neuroprotective properties.
In Aim 3, we will test the in vivo efficacy of the most promising compound. We will determine whether the application of this compound reduces the levels of early intraneuronal Ab deposits in an AD mouse model called 3xTg-AD mice. Optimized compounds might be developed into therapeutic agents for AD. Since an important property of our selected compounds is binding to Ab aggregates, they might also be developed into amyloid imaging agents too.

Public Health Relevance

The amyloid-beta protein is toxic to brain cells and is widely considered a drug target for Alzheimer's disease treatment. We will use emerging chemical and cell biological technologies to find small molecular compounds that block the toxic effect of the amyloid-beta protein. These compounds can be developed into therapeutic agents for Alzheimer's disease or into imaging agents for radiological diagnosis of Alzheimer's disease, a leading cause of dementia worldwide. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AG031362-01A1
Application #
7528195
Study Section
Special Emphasis Panel (ZRG1-MNPS-C (09))
Program Officer
Buckholtz, Neil
Project Start
2008-09-01
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
1
Fiscal Year
2008
Total Cost
$161,500
Indirect Cost
Name
University of California Davis
Department
Pathology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Hong, Hyun-Seok; Maezawa, Izumi; Petrlova, Jitka et al. (2015) Tomoregulin (TMEFF2) Binds Alzheimer's Disease Amyloid-? (A?) Oligomer and A?PP and Protects Neurons from A?-Induced Toxicity. J Alzheimers Dis 48:731-43
Horiuchi, Makoto; Maezawa, Izumi; Itoh, Aki et al. (2012) Amyloid ?1-42 oligomer inhibits myelin sheet formation in vitro. Neurobiol Aging 33:499-509
Maezawa, Izumi; Zimin, Pavel I; Wulff, Heike et al. (2011) Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. J Biol Chem 286:3693-706
Petrlova, Jitka; Hong, Hyun-Seok; Bricarello, Daniel A et al. (2011) A differential association of Apolipoprotein E isoforms with the amyloid-ýý oligomer in solution. Proteins 79:402-16
Hong, Hyun-Seok; Maezawa, Izumi; Budamagunta, Madhu et al. (2010) Candidate anti-A beta fluorene compounds selected from analogs of amyloid imaging agents. Neurobiol Aging 31:1690-9
Lulevich, Valentin; Zimmer, Christopher C; Hong, Hyun-seok et al. (2010) Single-cell mechanics provides a sensitive and quantitative means for probing amyloid-beta peptide and neuronal cell interactions. Proc Natl Acad Sci U S A 107:13872-7