Trichostatin A ameliorates Alzheimer's disease-related pathology and cognitive deficits by increasing albumin expression and Aβ clearance in APP/PS1 mice.
APP/PS1 mice
Albumin
Amyloid β clearance
Learning and memory
Microglia
Trichostatin A
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
04 01 2021
04 01 2021
Historique:
received:
24
06
2020
accepted:
08
12
2020
entrez:
5
1
2021
pubmed:
6
1
2021
medline:
25
6
2021
Statut:
epublish
Résumé
Alzheimer's disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms. Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS. TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers. These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.
Sections du résumé
BACKGROUND
Alzheimer's disease (AD) is an intractable neurodegenerative disorder in the elderly population, currently lacking a cure. Trichostatin A (TSA), a histone deacetylase inhibitor, showed some neuroprotective roles, but its pathology-improvement effects in AD are still uncertain, and the underlying mechanisms remain to be elucidated. The present study aims to examine the anti-AD effects of TSA, particularly investigating its underlying cellular and molecular mechanisms.
METHODS
Novel object recognition and Morris water maze tests were used to evaluate the memory-ameliorating effects of TSA in APP/PS1 transgenic mice. Immunofluorescence, Western blotting, Simoa assay, and transmission electron microscopy were utilized to examine the pathology-improvement effects of TSA. Microglial activity was assessed by Western blotting and transwell migration assay. Protein-protein interactions were analyzed by co-immunoprecipitation and LC-MS/MS.
RESULTS
TSA treatment not only reduced amyloid β (Aβ) plaques and soluble Aβ oligomers in the brain, but also effectively improved learning and memory behaviors of APP/PS1 mice. In vitro study suggested that the improvement of Aβ pathology by TSA was attributed to the enhancement of Aβ clearance, mainly by the phagocytosis of microglia, and the endocytosis and transport of microvascular endothelial cells. Notably, a meaningful discovery in the study was that TSA dramatically upregulated the expression level of albumin in cell culture, by which TSA inhibited Aβ aggregation and promoted the phagocytosis of Aβ oligomers.
CONCLUSIONS
These findings provide a new insight into the pathogenesis of AD and suggest TSA as a novel promising candidate for the AD treatment.
Identifiants
pubmed: 33397436
doi: 10.1186/s13195-020-00746-8
pii: 10.1186/s13195-020-00746-8
pmc: PMC7784383
doi:
Substances chimiques
Albumins
0
Amyloid beta-Peptides
0
Amyloid beta-Protein Precursor
0
Hydroxamic Acids
0
Presenilin-1
0
trichostatin A
3X2S926L3Z
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7Références
Proc Natl Acad Sci U S A. 2018 Nov 20;115(47):E11148-E11157
pubmed: 30397132
Neuropathol Appl Neurobiol. 2013 Feb;39(1):19-34
pubmed: 23039106
Neural Regen Res. 2020 Feb;15(2):293-301
pubmed: 31552902
J Cell Biol. 1964 Feb;20:271-9
pubmed: 14126872
Nature. 1998 Jan 22;391(6665):387-90
pubmed: 9450754
Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5
pubmed: 11438712
Autophagy. 2015 Apr 3;11(4):629-42
pubmed: 25919885
PLoS One. 2013 Dec 18;8(12):e84457
pubmed: 24367661
J Alzheimers Dis. 2009;18(1):131-9
pubmed: 19625751
Alzheimers Dement (N Y). 2019 Feb 26;5:61-69
pubmed: 30859122
J Clin Invest. 2016 Jan;126(1):123-36
pubmed: 26619118
J Biol Chem. 1996 Dec 20;271(51):32916-22
pubmed: 8955133
Clin Cancer Res. 2001 Apr;7(4):971-6
pubmed: 11309348
Life Sci. 2014 Mar 18;99(1-2):31-6
pubmed: 24486299
Nat Protoc. 2013 Dec;8(12):2531-7
pubmed: 24263092
Neurosci Res. 2014 Nov;88:39-48
pubmed: 25128386
Mol Cell Proteomics. 2004 Apr;3(4):327-44
pubmed: 14754989
Mol Neurobiol. 2019 Oct;56(10):7234-7245
pubmed: 31004319
Science. 1999 Oct 22;286(5440):735-41
pubmed: 10531052
J Alzheimers Dis. 2017;56(1):129-143
pubmed: 27911295
Neuron. 2018 Mar 7;97(5):1023-1031.e7
pubmed: 29518356
Mol Neurobiol. 2015 Feb;51(1):1-7
pubmed: 24733588
Brain Res. 1992 Jan 8;569(1):141-5
pubmed: 1611474
Nat Protoc. 2006;1(2):848-58
pubmed: 17406317
Brain. 2016 Mar;139(Pt 3):891-907
pubmed: 26747862
Brain Res Brain Res Rev. 1995 Mar;20(3):269-87
pubmed: 7550361
Front Neurosci. 2020 Sep 03;14:859
pubmed: 33013289
Neuroscientist. 2011 Apr;17(2):163-73
pubmed: 21330304
Science. 2002 Jul 19;297(5580):353-6
pubmed: 12130773
Blood Transfus. 2009 Oct;7(4):268-77
pubmed: 20011638
Comput Struct Biotechnol J. 2019 Jun 26;17:963-971
pubmed: 31360335
Aliment Pharmacol Ther. 2002 Dec;16 Suppl 5:6-11
pubmed: 12423448
J Alzheimers Dis. 2014;41(4):1193-205
pubmed: 24844691
PLoS One. 2008 Jul 30;3(7):e2829
pubmed: 18665237
J Neurosci. 2009 Apr 1;29(13):4252-62
pubmed: 19339619
Nat Rev Neurol. 2015 Aug;11(8):457-70
pubmed: 26195256
Trends Neurosci. 2017 Jun;40(6):347-357
pubmed: 28494972
Proc Natl Acad Sci U S A. 1982 Sep;79(17):5254-7
pubmed: 6182563
J Neurosci. 2013 Dec 4;33(49):19276-83
pubmed: 24305823
Neuron. 2004 Aug 5;43(3):333-44
pubmed: 15294142
Electrophoresis. 2002 Apr;23(7-8):1185-96
pubmed: 11981868
Pharmacol Biochem Behav. 2014 Nov;126:83-9
pubmed: 25242807
J Cancer. 2018 Feb 28;9(6):987-997
pubmed: 29581778
Lymphology. 2004 Jun;37(2):65-72
pubmed: 15328759
Neurotox Res. 2018 Oct;34(3):733-748
pubmed: 29626319
Mar Drugs. 2015 Sep 16;13(9):5828-46
pubmed: 26389923
J Neuropathol Exp Neurol. 1993 Nov;52(6):594-600
pubmed: 8229078
Proteomics Clin Appl. 2007 Sep;1(9):1004-15
pubmed: 21136753
Expert Opin Drug Discov. 2020 Apr;15(4):397-401
pubmed: 31847616
Int J Geriatr Psychiatry. 2006 Apr;21(4):344-8
pubmed: 16534775
J Am Chem Soc. 2017 Nov 1;139(43):15437-15445
pubmed: 28930473
Neuropsychopharmacology. 2015 Sep;40(10):2307-16
pubmed: 25837283
Proc Natl Acad Sci U S A. 2018 Jul 10;115(28):E6640-E6649
pubmed: 29946028
J Neurosci Res. 2011 Jun;89(6):808-14
pubmed: 21374699
Biochem Pharmacol. 2004 Aug 15;68(4):753-60
pubmed: 15276083
Curr Alzheimer Res. 2014;11(10):1002-11
pubmed: 25387339
Neurobiol Aging. 2008 Nov;29(11):1607-18
pubmed: 17544172
Nat Rev Drug Discov. 2002 Apr;1(4):287-99
pubmed: 12120280
Neuron. 2013 Sep 4;79(5):873-86
pubmed: 24012002
Mol Neurobiol. 2007 Jun;35(3):203-16
pubmed: 17917109
Br J Pharmacol. 2019 Sep;176(18):3447-3463
pubmed: 30710367
J Antibiot (Tokyo). 1976 Jan;29(1):1-6
pubmed: 931784