Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington's disease.
Brain delivery
Cholesterol
Cognitive decline
Huntington's disease
Nanoparticles
Journal
Pharmacological research
ISSN: 1096-1186
Titre abrégé: Pharmacol Res
Pays: Netherlands
ID NLM: 8907422
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
12
04
2023
revised:
14
06
2023
accepted:
16
06
2023
medline:
21
8
2023
pubmed:
20
6
2023
entrez:
19
6
2023
Statut:
ppublish
Résumé
Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing ("early treatment") or reversing ("late treatment") HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic ("early treatment") or symptomatic ("late treatment") stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments ("2 cycle treatment") lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors.
Identifiants
pubmed: 37336430
pii: S1043-6618(23)00179-2
doi: 10.1016/j.phrs.2023.106823
pmc: PMC10463277
pii:
doi:
Substances chimiques
Cholesterol
97C5T2UQ7J
Types de publication
Meta-Analysis
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
106823Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors report no competing interests.
Références
PLoS One. 2012;7(12):e49838
pubmed: 23284626
Nat Rev Drug Discov. 2023 Jun;22(6):431-434
pubmed: 37198334
Biol Psychiatry. 2018 May 15;83(10):800-809
pubmed: 29174478
J Neurosci. 2010 Aug 11;30(32):10844-50
pubmed: 20702713
PLoS One. 2012;7(12):e50717
pubmed: 23284644
Neurobiol Dis. 2013 Jul;55:37-43
pubmed: 23557875
Prog Neurobiol. 2007 Apr;81(5-6):253-71
pubmed: 17169479
Front Aging Neurosci. 2021 Jul 08;13:696778
pubmed: 34305573
Arterioscler Thromb Vasc Biol. 2004 May;24(5):806-15
pubmed: 14764421
EMBO Mol Med. 2020 Oct 7;12(10):e12519
pubmed: 32959531
EMBO Rep. 2014 Oct;15(10):1036-52
pubmed: 25223281
Mov Disord. 2011 Apr;26(5):862-9
pubmed: 21394785
J Neurophysiol. 2015 Apr 1;113(7):2953-66
pubmed: 25673747
Int J Pharm. 2018 May 30;543(1-2):300-310
pubmed: 29608954
EMBO Mol Med. 2015 Nov 20;7(12):1547-64
pubmed: 26589247
Brain. 2016 Mar;139(Pt 3):953-70
pubmed: 26912634
Brain. 2019 Aug 1;142(8):2432-2450
pubmed: 31286142
J Clin Invest. 2019 May 6;129(6):2390-2403
pubmed: 31063986
Trends Neurosci. 2022 May;45(5):401-414
pubmed: 35184896
Neurobiol Dis. 2007 Oct;28(1):133-42
pubmed: 17702587
Proc Natl Acad Sci U S A. 2009 Aug 25;106(34):14664-9
pubmed: 19667174
J Neurochem. 1995 Feb;64(2):895-901
pubmed: 7830084
J Control Release. 2021 Feb 10;330:587-598
pubmed: 33412229
Neurodegener Dis. 2017;17(6):313-322
pubmed: 29073635
Neuron. 2016 Mar 2;89(5):910-26
pubmed: 26938440
J Control Release. 2007 Sep 11;122(1):1-9
pubmed: 17651855
Neuron. 2012 Jun 21;74(6):1031-44
pubmed: 22726834
J Control Release. 2014 Mar 10;177:96-107
pubmed: 24417968
Brain. 2008 Nov;131(Pt 11):2851-9
pubmed: 18772220
Brain. 2021 Nov 29;144(10):3175-3190
pubmed: 33974044
Front Hum Neurosci. 2018 Jun 21;12:250
pubmed: 29977198
Prog Neurobiol. 2013 Nov;110:2-28
pubmed: 24036231
JCI Insight. 2022 Oct 24;7(20):
pubmed: 36278490
Brain Pathol. 2016 Nov;26(6):726-740
pubmed: 27529157
Toxicol Pathol. 2009 Dec;37(7):882-6
pubmed: 19770348
Mol Cancer Res. 2021 Feb;19(2):288-300
pubmed: 33139505
Neurobiol Dis. 2017 Feb;98:66-76
pubmed: 27913290
ACS Chem Neurosci. 2020 Feb 5;11(3):367-372
pubmed: 31860272
Nat Med. 2019 Jul;25(7):1131-1142
pubmed: 31263285
Physiol Rev. 2010 Jul;90(3):905-81
pubmed: 20664076
Brain Neurosci Adv. 2020 Nov 17;4:2398212820972599
pubmed: 33283053
Hum Mol Genet. 2016 Sep 1;25(17):3654-3675
pubmed: 27378694
Cell Death Differ. 2015 Apr;22(4):690-702
pubmed: 25301063
Neurosci Lett. 2011 May 2;494(3):245-9
pubmed: 21406216
J Biol Chem. 2006 May 5;281(18):12799-808
pubmed: 16524875
Trends Neurosci. 2010 Nov;33(11):513-23
pubmed: 20850189
Hum Mol Genet. 2007 Sep 15;16(18):2187-98
pubmed: 17613541