Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer's disease pathology in mice.
Wnt signalling
amyloid plaques
mTor pathway
microdialysis
neurofibrillary tangles
repurposed drugs
Journal
Frontiers in pharmacology
ISSN: 1663-9812
Titre abrégé: Front Pharmacol
Pays: Switzerland
ID NLM: 101548923
Informations de publication
Date de publication:
2022
2022
Historique:
received:
06
04
2022
accepted:
28
06
2022
entrez:
2
9
2022
pubmed:
3
9
2022
medline:
3
9
2022
Statut:
epublish
Résumé
All drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer's disease (AD) patients. In this study, we repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting synaptic formation (i.e., Wnt signaling) and cellular clearance (i.e., autophagic) pathways respectively, to test their therapeutic potential for attenuating AD-related pathology. We characterized our 3xTg AD mouse colony to select timepoints for separate and combinatorial treatment of both drugs while collecting cerebrospinal fluid (CSF) using an optimized microdialysis method. We found that treatment with Fasudil reduced Aβ at early and later stages of AD, whereas administration of Lonafarnib had no effect on Aβ, but did reduce tau, at early stages of the disease. Induction of autophagy led to increased size of amyloid plaques when administered at late phases of the disease. We show that combinatorial treatment with both drugs was effective at reducing intraneuronal Aβ and led to improved cognitive performance in mice. These findings lend support to regulating Wnt and autophagic pathways in order to attenuate AD-related pathology.
Identifiants
pubmed: 36052130
doi: 10.3389/fphar.2022.913971
pii: 913971
pmc: PMC9426773
doi:
Types de publication
Journal Article
Langues
eng
Pagination
913971Informations de copyright
Copyright © 2022 Bjorkli, Hemler, Julian, Sandvig and Sandvig.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Références
Nat Biotechnol. 2004 May;22(5):589-94
pubmed: 15064769
PLoS One. 2011;6(9):e25416
pubmed: 21980451
PLoS One. 2014 Sep 19;9(9):e107447
pubmed: 25238609
Neurosci Lett. 1992 Nov 23;147(1):58-62
pubmed: 1336152
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5274-9
pubmed: 10220456
Genes Dev. 2003 Aug 1;17(15):1829-34
pubmed: 12869586
Arch Neurol. 2009 May;66(5):638-45
pubmed: 19433664
J Alzheimers Dis. 2014;42(4):1209-20
pubmed: 25024312
Sci Adv. 2019 Jun 26;5(6):eaaw6404
pubmed: 31249873
Int J Geriatr Psychiatry. 2002 Feb;17(2):146-9
pubmed: 11813277
Mol Psychiatry. 2014 Jan;19(1):88-98
pubmed: 23164821
Alzheimers Dement. 2016 Jan;12(1):60-4
pubmed: 26710325
Front Neurosci. 2019 Jan 10;12:1017
pubmed: 30686983
Arch Gen Psychiatry. 2012 Jan;69(1):98-106
pubmed: 22213792
Nat Rev Genet. 2004 Sep;5(9):691-701
pubmed: 15372092
Neuron. 2005 Mar 3;45(5):675-88
pubmed: 15748844
Prog Neurobiol. 2005 Feb;75(3):161-205
pubmed: 15882774
Neurobiol Dis. 2017 Nov;107:41-56
pubmed: 27425887
Histopathology. 2001 Feb;38(2):120-34
pubmed: 11207825
Sci Transl Med. 2019 Mar 27;11(485):
pubmed: 30918111
Alzheimers Dement. 2018 Mar;14(3):306-317
pubmed: 29055813
Acta Neuropathol. 1991;82(4):239-59
pubmed: 1759558
Exp Ther Med. 2018 Nov;16(5):3929-3938
pubmed: 30344671
Pharmacol Biochem Behav. 2002 Jan-Feb;71(1-2):277-82
pubmed: 11812533
PLoS One. 2015 Nov 05;10(11):e0142340
pubmed: 26540269
Biotech Histochem. 2002 Mar;77(2):95-103
pubmed: 12083391
Oncogene. 2015 Aug 27;34(35):4613-23
pubmed: 25500539
Neurobiol Aging. 2020 May;89:41-54
pubmed: 31982202
Neurobiol Dis. 2011 Jul;43(1):38-45
pubmed: 21296668
Front Neurosci. 2022 Jan 24;15:785276
pubmed: 35140584
Nat Methods. 2019 Dec;16(12):1226-1232
pubmed: 31570887
Dev Cell. 2007 Jan;12(1):129-41
pubmed: 17199046
Nat Neurosci. 2021 Jun;24(6):863-872
pubmed: 33859438
Curr Biol. 2011 Oct 25;21(20):R837-8
pubmed: 22032182
Med Sci Monit. 2017 Feb 14;23:801-808
pubmed: 28193995
Front Immunol. 2014 Aug 20;5:403
pubmed: 25191326
Drugs Aging. 2012 May 1;29(5):335-42
pubmed: 22500970
J Biol Chem. 2010 Apr 23;285(17):13107-20
pubmed: 20178983
Microcirculation. 2003 Dec;10(6):463-70
pubmed: 14745459
Oncogene. 2006 Oct 16;25(48):6361-72
pubmed: 17041622
J Biol Chem. 2011 Mar 18;286(11):8924-32
pubmed: 21266573
Cancer Res. 2005 Oct 15;65(20):9109-12
pubmed: 16230362
Mol Med Rep. 2015 Nov;12(5):7615-22
pubmed: 26459718
J Neurosurg. 2009 Jun;110(6):1227-37
pubmed: 19216653
J Alzheimers Dis. 2021;84(4):1781-1794
pubmed: 34719495
Front Hum Neurosci. 2018 Nov 09;12:442
pubmed: 30473660
Brain. 2012 Jul;135(Pt 7):2169-77
pubmed: 22689910
NeuroRx. 2005 Jan;2(1):3-14
pubmed: 15717053
Front Aging Neurosci. 2020 Sep 02;12:272
pubmed: 32982716
J Neurosci. 2013 Dec 4;33(49):19086-98
pubmed: 24305806
Exp Neurol. 1994 May;127(1):23-36
pubmed: 8200435
Neurobiol Aging. 2013 Jun;34(6):1564-80
pubmed: 23273573
Proc Natl Acad Sci U S A. 2015 May 19;112(20):6503-8
pubmed: 25941390
Transl Psychiatry. 2018 Sep 20;8(1):179
pubmed: 30232325
PLoS One. 2012;7(4):e33606
pubmed: 22496755
Cell. 2016 Feb 11;164(4):603-15
pubmed: 26871627
Lab Anim (NY). 2017 May 22;46(6):255-257
pubmed: 28530691
Neuron. 2017 Mar 8;93(5):1015-1034
pubmed: 28279350
Behav Brain Res. 2016 Sep 15;311:54-69
pubmed: 27185734
Nat Rev Neurosci. 2020 Mar;21(3):153-168
pubmed: 32042144
Nat Cell Biol. 2001 Jul;3(7):683-6
pubmed: 11433302
Mol Neurodegener. 2019 Aug 2;14(1):32
pubmed: 31375134
Front Mol Neurosci. 2019 Aug 22;12:203
pubmed: 31507373
J Neurochem. 2007 Jan;100(2):314-23
pubmed: 17241154
Nat Rev Neurosci. 2009 Dec;10(12):842-9
pubmed: 19888283
Neuron. 2003 Jul 31;39(3):409-21
pubmed: 12895417
Neurology. 2002 Jun 25;58(12):1791-800
pubmed: 12084879
Drug Metab Pharmacokinet. 2002;17(5):395-407
pubmed: 15618691
Psychol Bull. 1992 Jul;112(1):155-9
pubmed: 19565683