Abstract
Alzheimer’s disease (AD) is characterized by impaired clearance of amyloid beta (Aβ) peptides, leading to the accumulation of Aβ in the brain and subsequent neurodegeneration and cognitive impairment. ApoE plays a critical role in the proteolytic degradation of soluble forms of Aβ. This effect is dependent upon lipidation of ApoE by ABCA1-mediated transfer of phospholipids and cholesterol. ApoE and ABCA1 are induced by the action of the RXR agonist, bexarotene. We have previously shown that bexarotene reduces Aβ levels in AD mouse models and we have hypothesized that this effect requires ABCA1-mediated lipidation of ApoE. To test this hypothesis, we crossed ABCA1-deficient (ABCA1 KO) mice with the APP/PS1 model of AD. Aged ABCA1 WT and ABCA1 KO APP/PS1 mice were treated for 7 days with vehicle or bexarotene (100 mg/kg/day). Bexarotene reduced levels of soluble Aβ 1–40 and 1–42 in the hippocampus of ABCA1 WT but not ABCA1 KO APP/PS1 mice. In contrast, insoluble levels of Aβ, and plaque loads were unaffected by bexarotene in this study. ABCA1 KO mice had increased levels of inflammation compared with ABCA1 WT mice. Bexarotene also increased most inflammatory gene markers evaluated. The effect of bexarotene on microglial inflammatory profiles, however, was independent of ABCA1 genotype. Importantly, bexarotene ameliorated deficits in novel object recognition in ABCA1 WT but not ABCA1 KO APP/PS1 mice. These data indicate that ABCA1-induced lipidation of ApoE is necessary for the ability of bexarotene to clear hippocampal soluble Aβ and ameliorate cognitive deficits.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM (2006) Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 12:856–861
Cameron B, Tse W, Lamb R, Li X, Lamb BT, Landreth GE (2012) Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer’s disease. J Neurosci: OFF J Soc Neurosci 32:15112–15123
Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3:89ra57
Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335:1503–1506
De Nardo D, Labzin LI, Kono H, Seki R, Schmidt SV, Beyer M, Xu D, Zimmer S, Lahrmann C, Schildberg FA, Vogelhuber J, Kraut M, Ulas T, Kerksiek A, Krebs W, Bode N, Grebe A, Fitzgerald ML, Hernandez NJ, Williams BR, Knolle P, Kneilling M, Rocken M, Lutjohann D, Wright SD, Schultze JL, Latz E (2014) High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nat Immunol 15:152–160
Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, Chan J, Fan J, Collins J, Wellington CL (2010) ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 mice. J Biol Chem 285:34144–34154
El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, Luster AD (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13:432–438
Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, Kitazawa M, Matusow B, Nguyen H, West BL, Green KN (2014) Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82:380–397
Fitz NF, Cronican AA, Saleem M, Fauq AH, Chapman R, Lefterov I, Koldamova R (2012) Abca1 deficiency affects Alzheimer’s disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J Neurosci: OFF J Soc Neurosci 32:13125–13136
Fitz NF, Cronican AA, Lefterov I, Koldamova R (2013) Comment on ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 340:924-c
Hirsch-Reinshagen V, Zhou S, Burgess BL, Bernier L, McIsaac SA, Chan JY, Tansley GH, Cohn JS, Hayden MR, Wellington CL (2004) Deficiency of ABCA1 impairs apolipoprotein E metabolism in brain. J Biol chem 279:41197–41207
Hirsch-Reinshagen V, Maia LF, Burgess BL, Blain JF, Naus KE, McIsaac SA, Parkinson PF, Chan JY, Tansley GH, Hayden MR, Poirier J, Van Nostrand W, Wellington CL (2005) The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J Biol Chem 280:43243–43256
Hottman DA, Chernick D, Cheng S, Wang Z, Li L (2014) HDL and cognition in neurodegenerative disorders. Neurobiol Dis 72(Pt A):22–36
Jan A, Karasinska JM, Kang MH, de Haan W, Ruddle P, Kaur A, Connolly C, Leavitt BR, Sorensen PH, Hayden MR (2015) Direct intracerebral delivery of a miR-33 antisense oligonucelotide into mouse brain increases brain ABCA1 expression. Neurosci Lett 598:66–72
Jankowsky JL, Slunt HH, Ratovitski T, Jenkins NA, Copeland NG, Borchelt DR (2001) Co-expression of multiple transgenes in mouse CNS: a comparison of strategies. Biomol Eng 17:157–165
Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58:681–693
Karasinska JM, de Haan W, Franciosi S, Ruddle P, Fan J, Kruit JK, Stukas S, Lutjohann D, Gutmann DH, Wellington CL, Hayden MR (2013) ABCA1 influences neuroinflammation and neuronal death. Neurobiol Dis 54:445–455
Koldamova R, Staufenbiel M, Lefterov I (2005) Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 280:43224–43235
Koldamova R, Fitz NF, Lefterov I (2010) The role of ATP-binding cassette transporter A1 in Alzheimer’s disease and neurodegeneration. Biochim Biophys Acta 1801:824–830
Landreth GE, Cramer PE, Lakner MM, Cirrito JR, Wesson DW, Brunden KR, Wilson DA (2013) Response to comments on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340:924-g
Mandrekar-Colucci S, Karlo JC, Landreth GE (2012) Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J Neurosci Off J Soc Neurosci 32:10117–10128
Palop JJ, Mucke L (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 13:812–818
Price AR, Xu G, Siemienski ZB, Smithson LA, Borchelt DR, Golde TE, Felsenstein KM (2013) Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340:924-d
Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK, Ring RH, Kirksey Y, Aschmies S, Xu J, Kubek K, Hirst WD, Gonzales C, Chen Y, Murphy E, Leonard S, Vasylyev D, Oganesian A, Martone RL, Pangalos MN, Reinhart PH, Jacobsen JS (2007) The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease. Mol Cell Neurosci 34:621–628
Saijo K, Crotti A, Glass CK (2013) Regulation of microglia activation and deactivation by nuclear receptors. Glia 61:104–111
Savage JC, Jay T, Goduni E, Quigley C, Mariani MM, Malm T, Ransohoff RM, Lamb BT, Landreth GE (2015) Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. J Neurosci: OFF J Soc Neurosci 35:6532–6543
Skerrett R, Malm T, Landreth G (2014) Nuclear receptors in neurodegenerative diseases. Neurobiol Dis 72(Pt A):104–116
Tai LM, Koster KP, Luo J, Lee SH, Wang YT, Collins NC, Ben Aissa M, Thatcher GR, LaDu MJ (2014) Amyloid-beta Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo. J Biol Chem 289:30538–30555
Tesseur I, Lo AC, Roberfroid A, Dietvorst S, Van Broeck B, Borgers M, Gijsen H, Moechars D, Mercken M, Kemp J, D’Hooge R, De Strooper B (2013) Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340:924-e
Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, Duman RS, Flavell RA (2008) Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14:681–687
Veeraraghavalu K, Zhang C, Miller S, Hefendehl JK, Rajapaksha TW, Ulrich J, Jucker M, Holtzman DM, Tanzi RE, Vassar R, Sisodia SS (2013) Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340:924-f
Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10:241–252
Wahrle SE, Jiang H, Parsadanian M, Legleiter J, Han X, Fryer JD, Kowalewski T, Holtzman DM (2004) ABCA1 is required for normal central nervous system ApoE levels and for lipidation of astrocyte-secreted apoE. J Biol Chem 279:40987–40993
Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, Paul SM, Holtzman DM (2005) Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem 280:43236–43242
Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM (2008) Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118:671–682
Wildsmith KR, Holley M, Savage JC, Skerrett R, Landreth GE (2013) Evidence for impaired amyloid beta clearance in Alzheimer’s disease. Alzheimers Res Ther 5:33
Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, Vinters HV, Tontonoz P (2007) Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver x receptors. Proc Natl Acad Sci U S A 104:10601–10606
Conflict of Interest
G.E.L. is a co-founder of Rexceptor, Inc., a biotechnology company developing RXR agonists for the treatment of neurodegenerative diseases. All other authors declare no conflicts of interest.
Ethical Approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Corona, A.W., Kodoma, N., Casali, B.T. et al. ABCA1 is Necessary for Bexarotene-Mediated Clearance of Soluble Amyloid Beta from the Hippocampus of APP/PS1 Mice. J Neuroimmune Pharmacol 11, 61–72 (2016). https://doi.org/10.1007/s11481-015-9627-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-015-9627-8