Peripheral administration of nanomicelle-encapsulated anti-Aβ oligomer fragment antibody reduces various toxic Aβ species in the brain.
Alzheimer’s disease
Amyloid β oligomer
Polymeric nanomicelle
Pyroglutamated amyloid β
Journal
Journal of nanobiotechnology
ISSN: 1477-3155
Titre abrégé: J Nanobiotechnology
Pays: England
ID NLM: 101152208
Informations de publication
Date de publication:
31 Jan 2023
31 Jan 2023
Historique:
received:
13
06
2022
accepted:
07
01
2023
entrez:
1
2
2023
pubmed:
2
2
2023
medline:
3
2
2023
Statut:
epublish
Résumé
Although a large amount of evidence has revealed that amyloid β (Aβ), especially Aβ oligomers, protofibrils, and pyroglutamated Aβs, participate primarily in the pathophysiological processes of Alzheimer's disease, most clinical trials of anti-Aβ antibody therapy have never acquired successful efficacy in human clinical trials, partly because peripheral administration of antibody medications was unable to deliver sufficient amounts of the molecules to the brain. Recently, we developed polymeric nanomicelles capable of passing through the blood-brain barrier that function as chaperones to deliver larger amounts of heavy molecules to the brain. Herein, we aimed to evaluate the efficacy of newly developed antibody 6H4 fragments specific to Aβ oligomers encapsulated in polymeric nanomicelles on the development of Alzheimer's disease pathology in Alzheimer's disease model mice at the age of emergence of early Alzheimer's disease pathology. During the 10-week administration of 6H4 antibody fragments in polymeric nanomicelles, a significant reduction in the amounts of various toxic Aβ species, such as Aβ oligomers, toxic Aβ conformers, and pyroglutamated Aβs in the brain was observed. In addition, immunohistochemistry indicated inhibition of diameters of Aβ plaques, Aβ-antibody immunoreactive areas, and also plaque core formation. Behavioral analysis of the mice model revealed that the 6H4 fragments-polymeric nanomicelle group was significantly better at maintaining long-term spatial reference memory in the probe and platform tests of the water maze, thereby indicating inhibition of the pathophysiological process of Alzheimer's disease. The results indicated that the strategy of reducing toxic Aβ species in early dementia owing to Alzheimer's disease by providing sufficient antibodies in the brain may modify Alzheimer's disease progression.
Sections du résumé
BACKGROUND
BACKGROUND
Although a large amount of evidence has revealed that amyloid β (Aβ), especially Aβ oligomers, protofibrils, and pyroglutamated Aβs, participate primarily in the pathophysiological processes of Alzheimer's disease, most clinical trials of anti-Aβ antibody therapy have never acquired successful efficacy in human clinical trials, partly because peripheral administration of antibody medications was unable to deliver sufficient amounts of the molecules to the brain. Recently, we developed polymeric nanomicelles capable of passing through the blood-brain barrier that function as chaperones to deliver larger amounts of heavy molecules to the brain. Herein, we aimed to evaluate the efficacy of newly developed antibody 6H4 fragments specific to Aβ oligomers encapsulated in polymeric nanomicelles on the development of Alzheimer's disease pathology in Alzheimer's disease model mice at the age of emergence of early Alzheimer's disease pathology.
RESULTS
RESULTS
During the 10-week administration of 6H4 antibody fragments in polymeric nanomicelles, a significant reduction in the amounts of various toxic Aβ species, such as Aβ oligomers, toxic Aβ conformers, and pyroglutamated Aβs in the brain was observed. In addition, immunohistochemistry indicated inhibition of diameters of Aβ plaques, Aβ-antibody immunoreactive areas, and also plaque core formation. Behavioral analysis of the mice model revealed that the 6H4 fragments-polymeric nanomicelle group was significantly better at maintaining long-term spatial reference memory in the probe and platform tests of the water maze, thereby indicating inhibition of the pathophysiological process of Alzheimer's disease.
CONCLUSIONS
CONCLUSIONS
The results indicated that the strategy of reducing toxic Aβ species in early dementia owing to Alzheimer's disease by providing sufficient antibodies in the brain may modify Alzheimer's disease progression.
Identifiants
pubmed: 36721182
doi: 10.1186/s12951-023-01772-y
pii: 10.1186/s12951-023-01772-y
pmc: PMC9888736
doi:
Substances chimiques
Amyloid beta-Peptides
0
Antibodies
0
Polymers
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
36Subventions
Organisme : Japan Society for the Promotion of Science
ID : KAKENHI grant 19K07836
Organisme : Japan Society for the Promotion of Science
ID : KAKENHI grant 20K07798
Organisme : Japan Agency for Medical Research and Development
ID : 18dm0107063h0003
Organisme : Japan Agency for Medical Research and Development
ID : JP19dm0107063h0004
Organisme : Japan Agency for Medical Research and Development
ID : JP20dm0107063h0005
Informations de copyright
© 2023. The Author(s).
Références
Neurobiol Dis. 2010 Jan;37(1):13-25
pubmed: 19664713
Science. 2002 Oct 25;298(5594):789-91
pubmed: 12399581
Nat Med. 2008 Aug;14(8):837-42
pubmed: 18568035
J Chem Inf Model. 2017 Nov 27;57(11):2811-2821
pubmed: 29099594
Neuron. 2012 Dec 6;76(5):908-20
pubmed: 23217740
Brain Pathol. 2020 Jan;30(1):36-45
pubmed: 31099449
Acta Neuropathol. 2020 Dec;140(6):811-830
pubmed: 32926214
Sci Rep. 2018 Apr 23;8(1):6412
pubmed: 29686315
J Alzheimers Dis. 2013;34(1):203-13
pubmed: 23186988
Biomacromolecules. 2016 Feb 8;17(2):446-53
pubmed: 26691492
Life Sci. 2012 Dec 10;91(23-24):1177-86
pubmed: 22579764
J Neurosci. 2010 Apr 7;30(14):4845-56
pubmed: 20371804
N Engl J Med. 2021 May 6;384(18):1691-1704
pubmed: 33720637
J Am Chem Soc. 2004 Mar 3;126(8):2355-61
pubmed: 14982439
J Neurosci. 2002 Sep 15;22(18):7873-8
pubmed: 12223540
Angew Chem Int Ed Engl. 2009;48(29):5309-12
pubmed: 19294716
Sci Rep. 2016 Jul 04;6:29038
pubmed: 27374357
ACS Nano. 2020 Jun 23;14(6):6729-6742
pubmed: 32431145
Nature. 1982 Jun 24;297(5868):681-3
pubmed: 7088155
Biochemistry. 2006 Oct 17;45(41):12393-9
pubmed: 17029395
Nat Med. 2008 Oct;14(10):1106-11
pubmed: 18836460
Biochemistry. 2008 Jul 15;47(28):7405-13
pubmed: 18570439
Science. 2021 Aug 6;373(6555):624-626
pubmed: 34353940
J Phys Chem B. 2015 Aug 27;119(34):11196-202
pubmed: 25996452
Alzheimers Res Ther. 2016 May 12;8(1):18
pubmed: 27176461
Am J Pathol. 1999 Sep;155(3):853-62
pubmed: 10487842
Nat Rev Neurol. 2019 Feb;15(2):73-88
pubmed: 30610216
NeuroRx. 2005 Jan;2(1):3-14
pubmed: 15717053
Ann Neurol. 2008 Mar;63(3):377-87
pubmed: 18300294
Biomed Res Int. 2013;2013:984041
pubmed: 24063020
Nat Commun. 2017 Oct 17;8(1):1001
pubmed: 29042554
Sci Rep. 2019 Nov 22;9(1):17368
pubmed: 31757975
Nat Neurosci. 2007 May;10(5):615-22
pubmed: 17435755
Pharmacol Ther. 2005 Nov;108(2):129-48
pubmed: 16112736
Mol Neurobiol. 2019 Jul;56(7):4639-4652
pubmed: 30374941
Sci Rep. 2015 Sep 29;5:14624
pubmed: 26416689
Mol Neurodegener. 2016 Jun 30;11(1):48
pubmed: 27363697