Xanomeline derivative EUK1001 attenuates Alzheimer's disease pathology in a triple transgenic mouse model

Li,Ziyan; Jia,Kaili; Duan,Yale; Wang,Dong; Zhou,Zongli; Dong,Suzhen

doi:10.3892/mmr.2017.7502

Xanomeline derivative EUK1001 attenuates Alzheimer's disease pathology in a triple transgenic mouse model

Authors:
- Ziyan Li
- Kaili Jia
- Yale Duan
- Dong Wang
- Zongli Zhou
- Suzhen Dong
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Affiliations: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, P.R. China, Key Lab of Brain Functional Genomics, Shanghai Institute of Brain Functional Genomics, East China Normal University, Shanghai 200062, P.R. China
Published online on: September 18, 2017 https://doi.org/10.3892/mmr.2017.7502
Pages: 7835-7840

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Abstract

Agonists of M1 muscarinic acetylcholine receptors are promising therapeutic agents for the treatment of Alzheimer's disease (AD). An example of one of these agents is xanomeline, which has been a leading candidate, however induces various unwanted adverse effects. 3‑[3‑(3‑florophenyl‑2‑propyn‑1‑ylthio)‑1,2,5‑thiadiazol-4-yl]-1,2,5,6-tetrahydro‑1‑methylpyridine oxalate (EUK1001), a fluorinated derivative of xanomeline, has been demonstrated to attenuate AD‑like neurodegenerative pathology in presenilin‑deficient mice, which has no β‑amyloid (Aβ) pathology. The present study assessed the effect of EUK1001 on the behavioral performance of the 3xTg‑AD model of AD. EUK1001 treatment decreased cognitive deficits in male and female AD mice in the Morris water maze test and novel object recognition tasks. EUK1001 also decreased Aβ42, however not Aβ40 in the cortex and hippocampus of AD mice. EUK1001 may also alter amyloid precursor protein processing to a nonamyloidgenic pathway in vitro. These results demonstrate that EUK1001 may ameliorate the cognitive dysfunction of AD mice, possibly by reducing Aβ production. Therefore, EUK1001 may be an effective treatment for AD.

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1	Knapp MJ, Knopman DS, Solomon PR, Pendlebury WW, Davis CS and Gracon SI: A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. The Tacrine Study Group. JAMA. 271:985–991. 1994. View Article : Google Scholar : PubMed/NCBI
2	Nordberg A, Alafuzoff I and Winblad B: Nicotinic and muscarinic subtypes in the human brain: Changes with aging and dementia. J Neurosci Res. 31:103–111. 1992. View Article : Google Scholar : PubMed/NCBI
3	Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Bymaster FP, et al: Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease. Arch Neurol. 54:465–473. 1997. View Article : Google Scholar : PubMed/NCBI
4	Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A and LaFerla FM: M1 receptors play a central role in modulating AD-like pathology in transgenic mice. Neuron. 49:671–682. 2006. View Article : Google Scholar : PubMed/NCBI
5	Fisher A: M1 muscarinic agonists target major hallmarks of Alzheimer's disease-an update. Curr Alzheimer Res. 4:577–580. 2007. View Article : Google Scholar : PubMed/NCBI
6	Wang D, Yang L, Su J, Niu Y, Lei X, Xiong J, Cao X, Hu Y, Mei B and Hu JF: Attenuation of neurodegenerative phenotypes in Alzheimer-like presenilin 1/presenilin 2 conditional double knockout mice by EUK1001, a promising derivative of xanomeline. Biochem Biophys Res Commun. 410:229–234. 2011. View Article : Google Scholar : PubMed/NCBI
7	Cui Y, Wang D, Si W, Lv W, Niu Y, Lei X, Hu Y and Cao X: Enhancement of memory function in aged mice by a novel derivative of xanomeline. Cell Res. 18:1151–1153. 2008. View Article : Google Scholar : PubMed/NCBI
8	Cui YH, Si W, Yin L, An SM, Jin J, Deng SN and Cao XH: A novel derivative of xanomeline improved memory function in aged mice. Neurosci Bull. 24:251–257. 2008. View Article : Google Scholar : PubMed/NCBI
9	Zhang XL, Gong Q, Zhang S, Wang L, Hu Y, Shen H and Dong S: 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1,2, 5-thiadiazol-4-yl]-1,2,5,6-tetrahydro-1-methylpyridine oxalate, a novel xanomeline derivative, improves neural cells proliferation and survival in adult mice. Neural Regen Res. 7:24–30. 2012.PubMed/NCBI
10	Beglopoulos V, Sun X, Saura CA, Lemere CA, Kim RD and Shen J: Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. J Biol Chem. 279:46907–46914. 2004. View Article : Google Scholar : PubMed/NCBI
11	Feng R, Wang H, Wang J, Shrom D, Zeng X and Tsien JZ: Forebrain degeneration and ventricle enlargement caused by double knockout of Alzheimer's presenilin-1 and presenilin-2. Proc Natl Acad Sci USA. 101:8162–8167. 2004; View Article : Google Scholar : PubMed/NCBI
12	Saura CA, Choi SY, Beglopoulos V, Malkani S, Zhang D, Rao BS Shankaranarayana, Chattarji S, Kelleher RJ III, Kandel ER, Duff K, et al: Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. Neuron. 42:23–36. 2004. View Article : Google Scholar : PubMed/NCBI
13	Jiang X, Zhang D, Shi J, Chen Y, Zhang P and Mei B: Increased inflammatory response both in brain and in periphery in presenilin 1 and presenilin 2 conditional double knock-out mice. J Alzheimers Dis. 18:515–523. 2009. View Article : Google Scholar : PubMed/NCBI
14	Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y and LaFerla FM: Triple-transgenic model of Alzheimer's disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron. 39:409–421. 2003. View Article : Google Scholar : PubMed/NCBI
15	Clinton LK, Billings LM, Green KN, Caccamo A, Ngo J, Oddo S, McGaugh JL and LaFerla FM: Age-dependent sexual dimorphism in cognition and stress response in the 3×Tg-AD mice. Neurobiol Dis. 28:76–82. 2007. View Article : Google Scholar : PubMed/NCBI
16	Dong S, Li C, Wu P, Tsien JZ and Hu Y: Environment enrichment rescues the neurodegenerative phenotypes in presenilins-deficient mice. Eur J Neurosci. 26:101–112. 2007. View Article : Google Scholar : PubMed/NCBI
17	Haring R, Fisher A, Marciano D, Pittel Z, Kloog Y, Zuckerman A, Eshhar N and Heldman E: Mitogen-activated protein kinase-dependent and protein kinase C-dependent pathways link the m1 muscarinic receptor to beta-amyloid precursor protein secretion. J Neurochem. 71:2094–2103. 1998. View Article : Google Scholar : PubMed/NCBI
18	Caccamo A, Fisher A and LaFerla FM: M1 agonists as a potential disease-modifying therapy for Alzheimer's disease. Curr Alzheimer Res. 6:112–117. 2009. View Article : Google Scholar : PubMed/NCBI
19	HTL-9936 is a selective muscarinic M1 agonist designed to improve cognitive function in patients with AD and other diseases. http://newdrugapprovals.org/2014/05/05/htl-9936-is-a-selective-muscarinic-m1-agonist-designed-to-improve-cognitive-function-in-patients-with-ad-and-other-diseases/