Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the leading cause of dementia. Emerging evidence has recognized small, soluble oligomers of amyloid-?-peptide (A?Os) as the major toxic species for cognition impairment in AD. Furthermore, evidence has been accumulating that oxidative stress, biometal dyshomeostasis, and neuroinflammation may also contribute to the pathology of AD. Numerous small molecules targeting each of these risk factors have been developed and tested in preclinical and clinical trials, however, none of them has been approved by FDA as AD-modifying agents. This may suggest that one of the alternative and promising strategies is to use multifunctional ligands to tackle these risk factors simultaneously. Furthermore, evidence has increasingly underscored the important roles of cell membrane/lipid rafts (CM/LR) in the pathology of AD and CM/LR have been implicated to associate with all the identified risk factors in AD. This indicates that this relationship can be exploited therapeutically to develop strategic distinct multifunctional agents by incorporating this factor into molecular design. The overall goa of this proposal is to validate and develop more potent bivalent multifunctional A? oligomerization inhibitors (BMAOIs) that contain a multifunctional A?O-inhibitor with intrinsic antioxidant/metal chelating functions and a CM/LR anchor moiety as lead compounds for further preclinical studies. The central hypothesis of this application is that these BMAOIs will anchor the multifunctional A?O-inhibitor moiety inside, or in the vicinity of, CM/LR where A? oligomerization, Ab/biometal interactions, and oxidative stress occur to increase its local concentration and accessibility, thus enhancing its efficiency. Preliminary studies in our laboratory have reached the proof-of- concept of the BMAOIs strategy and resulted in the identification of two promising lead compounds for further optimization.
Three specific aims are proposed to achieve our objective in this application.
In aim 1, a series of BMAOIs will be designed and synthesized based on the newly identified lead compounds to modify and optimize the spacer domain, CM/LR anchor domain and A?O-inhibitor domain.
In aim 2, the designed BMAOIs will be evaluated in various in vitro assays including inhibition of A?O formation in association with protective activity in human neuroblastoma MC65 cells as well as neuroprotective effects on differentiated SH-SY5Y and mouse primary neurons. The co-localization of BMAOIs with CM/LR will also be investigated in MC65 cells and mouse primary neurons. In addition, antioxidant and metal complexation properties of selected BMAOIs will be tested.
In aim 3, potent BMAOIs that passed the selection criteria of aim 2 will be evaluated for their effects on cognition and A? pathology in transgenic TgCRND8 mice. The proposed research is innovative because we seek a new class of BMAOIs targeting A?Os, oxidative stress, A?/biometal interactions and CM/LR as novel pharmacological tools and potential AD-modifying agents. The outcome of this study would be a novel, validated, BMAOIs strategy available and ultimately benefit pharmacotherapy for AD.
|Saathoff, John M; Liu, Kai; Chojnacki, Jeremy E et al. (2016) Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer's Disease. Molecules 21:412|
|Gerenu, Gorka; Liu, Kai; Chojnacki, Jeremy E et al. (2015) Curcumin/melatonin hybrid 5-(4-hydroxy-phenyl)-3-oxo-pentanoic acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide ameliorates AD-like pathology in the APP/PS1 mouse model. ACS Chem Neurosci 6:1393-9|
|Chojnacki, Jeremy E; Liu, Kai; Saathoff, John M et al. (2015) Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer's disease. Bioorg Med Chem 23:7324-31|
|Liu, Kai; Chojnacki, Jeremy E; Wade, Emily E et al. (2015) Bivalent Compound 17MN Exerts Neuroprotection through Interaction at Multiple Sites in a Cellular Model of Alzheimer's Disease. J Alzheimers Dis 47:1021-33|
|Liu, Kai; Zhang, Shijun (2015) Highly Efficient Synthesis of 1,3-Dihydroxy-2-carboxycarbazole and Its Neuroprotective Effects. ACS Med Chem Lett 6:894-7|
|Marchetti, Carlo; Toldo, Stefano; Chojnacki, Jeremy et al. (2015) Pharmacologic Inhibition of the NLRP3 Inflammasome Preserves Cardiac Function After Ischemic and Nonischemic Injury in the Mouse. J Cardiovasc Pharmacol 66:1-8|
|Poklis, Justin L; Dempsey, Sara K; Liu, Kai et al. (2015) Identification of Metabolite Biomarkers of the Designer Hallucinogen 25I-NBOMe in Mouse Hepatic Microsomal Preparations and Human Urine Samples Associated with Clinical Intoxication. J Anal Toxicol 39:607-16|
|Marchetti, Carlo; Chojnacki, Jeremy; Toldo, Stefano et al. (2014) A novel pharmacologic inhibitor of the NLRP3 inflammasome limits myocardial injury after ischemia-reperfusion in the mouse. J Cardiovasc Pharmacol 63:316-22|
|Chojnacki, Jeremy E; Liu, Kai; Yan, Xing et al. (2014) Discovery of 5-(4-hydroxyphenyl)-3-oxo-pentanoic acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide as a neuroprotectant for Alzheimer's disease by hybridization of curcumin and melatonin. ACS Chem Neurosci 5:690-9|
|Liu, Kai; Chen, Jiangmin; Chojnacki, Jeremy et al. (2013) BF3Ã½Ã½OEt2-Promoted Concise Synthesis of Difluoroboron-Derivatized Curcumins from Aldehydes and 2,4-Pentanedione. Tetrahedron Lett 54:2070-2073|
Showing the most recent 10 out of 11 publications