Neuronally-directed Effects of RXR Activation in a Mouse Model of Alzheimer's Disease

Overview

Journal Sci Rep

Specialty Science

Date 2017 Feb 17

PMID 28205585

Citations 54

Authors

M M Mariani

T Malm

R Lamb

T R Jay

L Neilson

B Casali

L Medarametla

G E Landreth

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is characterized by extensive neuron loss that accompanies profound impairments in memory and cognition. We examined the neuronally directed effects of the retinoid X receptor agonist bexarotene in an aggressive model of AD. We report that a two week treatment of 3.5 month old 5XFAD mice with bexarotene resulted in the clearance of intraneuronal amyloid deposits. Importantly, neuronal loss was attenuated by 44% in the subiculum in mice 4 months of age and 18% in layer V of the cortex in mice 8 months of age. Moreover, bexarotene treatment improved remote memory stabilization in fear conditioned mice and improved olfactory cross habituation. These improvements in neuron viability and function were correlated with significant increases in the levels of post-synaptic marker PSD95 and the pre-synaptic marker synaptophysin. Moreover, bexarotene pretreatment improved neuron survival in primary 5XFAD neurons in vitro in response to glutamate-induced excitotoxicity. The salutary effects of bexarotene were accompanied by reduced plaque burden, decreased astrogliosis, and suppression of inflammatory gene expression. Collectively, these data provide evidence that bexarotene treatment reduced neuron loss, elevated levels of markers of synaptic integrity that was linked to improved cognition and in an aggressive model of AD.

Citing Articles

Recent Insights on the Role of Nuclear Receptors in Alzheimer's Disease: Mechanisms and Therapeutic Application.

Shan X, Li D, Yin H, Tao W, Zhou L, Gao Y Int J Mol Sci. 2025; 26(3).

PMID: 39940973 PMC: 11818835. DOI: 10.3390/ijms26031207.

Analysis of alcohol-metabolizing enzymes genetic variants and RAR/RXR expression in patients diagnosed with fetal alcohol syndrome: a case-control study.

Vieiros M, Navarro-Tapia E, Ramos-Triguero A, Garcia-Meseguer A, Martinez L, Garcia-Algar O BMC Genomics. 2024; 25(1):610.

PMID: 38886650 PMC: 11184718. DOI: 10.1186/s12864-024-10516-7.

Simple Fluorescence Labeling Method Enables Detection of Intracellular Distribution and Expression Level of Retinoid X Receptors.

Tanaka Y, Fujihara M, Takamura Y, Kawasaki M, Nakano S, Makishima M ACS Med Chem Lett. 2024; 15(5):640-645.

PMID: 38746897 PMC: 11089654. DOI: 10.1021/acsmedchemlett.4c00033.

Serial reversal learning in an olfactory discrimination task in 3xTg-AD mice.

Roddick K, Schellinck H, Brown R Learn Mem. 2023; 30(12):310-319.

PMID: 37977821 PMC: 10750865. DOI: 10.1101/lm.053840.123.

Oligodendrocyte progenitor cells in Alzheimer's disease: from physiology to pathology.

Zou P, Wu C, Liu T, Duan R, Yang L Transl Neurodegener. 2023; 12(1):52.

PMID: 37964328 PMC: 10644503. DOI: 10.1186/s40035-023-00385-7.

References

Murphy C . Loss of olfactory function in dementing disease. Physiol Behav. 1999; 66(2):177-82. DOI: 10.1016/s0031-9384(98)00262-5. View

Na S, Kang B, Chung S, Han S, Ma X, Trinchieri G . Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFkappaB. J Biol Chem. 1999; 274(12):7674-80. DOI: 10.1074/jbc.274.12.7674. View

Trujillo-Estrada L, Davila J, Sanchez-Mejias E, Sanchez-Varo R, Gomez-Arboledas A, Vizuete M . Early neuronal loss and axonal/presynaptic damage is associated with accelerated amyloid-β accumulation in AβPP/PS1 Alzheimer's disease mice subiculum. J Alzheimers Dis. 2014; 42(2):521-41. DOI: 10.3233/JAD-140495. View

Avrahami L, Farfara D, Shaham-Kol M, Vassar R, Frenkel D, Eldar-Finkelman H . Inhibition of glycogen synthase kinase-3 ameliorates β-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies. J Biol Chem. 2012; 288(2):1295-306. PMC: 3543013. DOI: 10.1074/jbc.M112.409250. View

Zhu J, Ning R, Lin X, Chai D, Xu C, Xie H . Retinoid X receptor agonists inhibit hypertension-induced myocardial hypertrophy by modulating LKB1/AMPK/p70S6K signaling pathway. Am J Hypertens. 2014; 27(8):1112-24. DOI: 10.1093/ajh/hpu017. View

Nenov M, Laezza F, Haidacher S, Zhao Y, Sadygov R, Starkey J . Cognitive enhancing treatment with a PPARγ agonist normalizes dentate granule cell presynaptic function in Tg2576 APP mice. J Neurosci. 2014; 34(3):1028-36. PMC: 3891946. DOI: 10.1523/JNEUROSCI.3413-13.2014. View

Veeraraghavalu K, Zhang C, Miller S, Hefendehl J, Rajapaksha T, Ulrich J . Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013; 340(6135):924-f. DOI: 10.1126/science.1235505. View

Tesseur I, Lo A, Roberfroid A, Dietvorst S, Van Broeck B, Borgers M . Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013; 340(6135):924-e. DOI: 10.1126/science.1233937. View

Kandalepas P, Sadleir K, Eimer W, Zhao J, Nicholson D, Vassar R . The Alzheimer's β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol. 2013; 126(3):329-52. PMC: 3753469. DOI: 10.1007/s00401-013-1152-3. View

10.

Christensen D, Bayer T, Wirths O . Intracellular Aß triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging. 2008; 31(7):1153-63. DOI: 10.1016/j.neurobiolaging.2008.07.022. View

11.

Chen L, Wang Y, Zhang J, Hao L, Guo H, Lou H . Bexarotene nanocrystal-Oral and parenteral formulation development, characterization and pharmacokinetic evaluation. Eur J Pharm Biopharm. 2013; 87(1):160-9. DOI: 10.1016/j.ejpb.2013.12.005. View

12.

Cummings J, Zhong K, Kinney J, Heaney C, Moll-Tudla J, Joshi A . Double-blind, placebo-controlled, proof-of-concept trial of bexarotene Xin moderate Alzheimer's disease. Alzheimers Res Ther. 2016; 8:4. PMC: 4731943. DOI: 10.1186/s13195-016-0173-2. View

13.

Mounier A, Georgiev D, Nam K, Fitz N, Castranio E, Wolfe C . Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity. J Neurosci. 2015; 35(34):11862-76. PMC: 4549399. DOI: 10.1523/JNEUROSCI.1001-15.2015. View

14.

Savage J, Jay T, Goduni E, Quigley C, Mariani M, Malm T . Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer's disease. J Neurosci. 2015; 35(16):6532-43. PMC: 4405560. DOI: 10.1523/JNEUROSCI.4586-14.2015. View

15.

Neumann H, Schweigreiter R, Yamashita T, Rosenkranz K, Wekerle H, Barde Y . Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. J Neurosci. 2002; 22(3):854-62. PMC: 6758473. View

16.

Nenov M, Tempia F, Denner L, Dineley K, Laezza F . Impaired firing properties of dentate granule neurons in an Alzheimer's disease animal model are rescued by PPARγ agonism. J Neurophysiol. 2014; 113(6):1712-26. PMC: 4359997. DOI: 10.1152/jn.00419.2014. View

17.

Lane-Donovan C, Philips G, Herz J . More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration. Neuron. 2014; 83(4):771-87. PMC: 4240629. DOI: 10.1016/j.neuron.2014.08.005. View

18.

Pickering M, Cumiskey D, OConnor J . Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol. 2005; 90(5):663-70. DOI: 10.1113/expphysiol.2005.030734. View

19.

Fitz N, Cronican A, Lefterov I, Koldamova R . Comment on "ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models". Science. 2013; 340(6135):924-c. PMC: 4086452. DOI: 10.1126/science.1235809. View

20.

Sastre M, Dewachter I, Rossner S, Bogdanovic N, Rosen E, Borghgraef P . Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma. Proc Natl Acad Sci U S A. 2006; 103(2):443-8. PMC: 1326151. DOI: 10.1073/pnas.0503839103. View