Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes.
Alzheimer’s disease
Amyloid
Matrix metalloproteinases
Multiphoton microscopy
Oxidative stress
Prediabetes
Type 2 diabetes
Journal
Fluids and barriers of the CNS
ISSN: 2045-8118
Titre abrégé: Fluids Barriers CNS
Pays: England
ID NLM: 101553157
Informations de publication
Date de publication:
07 Nov 2022
07 Nov 2022
Historique:
received:
01
06
2022
accepted:
26
09
2022
entrez:
8
11
2022
pubmed:
9
11
2022
medline:
10
11
2022
Statut:
epublish
Résumé
While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85-95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ. To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. Our data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.
Sections du résumé
BACKGROUND
BACKGROUND
While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85-95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ.
METHODS
METHODS
To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ
RESULTS
RESULTS
We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity.
CONCLUSIONS
CONCLUSIONS
Our data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.
Identifiants
pubmed: 36345028
doi: 10.1186/s12987-022-00380-6
pii: 10.1186/s12987-022-00380-6
pmc: PMC9639294
doi:
Substances chimiques
Amyloid beta-Peptides
0
Matrix Metalloproteinases
EC 3.4.24.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
88Subventions
Organisme : Medical Research Council
ID : MC_PC_19023
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/19/50/34436
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
Références
Neuron. 2005 Jul 21;47(2):191-199
pubmed: 16039562
J Neuropathol Exp Neurol. 2006 Nov;65(11):1082-9
pubmed: 17086105
Biochim Biophys Acta. 2016 May;1862(5):1037-46
pubmed: 26327684
Brain Res Brain Res Rev. 2003 Oct;43(2):207-23
pubmed: 14572915
Physiol Rep. 2019 Aug;7(16):
pubmed: 31448579
Brain. 2007 Sep;130(Pt 9):2310-9
pubmed: 17638859
Ann Neurol. 2014 Dec;76(6):845-61
pubmed: 25204284
Ann Neurol. 2019 Aug;86(2):279-292
pubmed: 31152566
Acta Neuropathol Commun. 2020 Jul 6;8(1):99
pubmed: 32631441
Aging (Albany NY). 2020 Dec 3;13(1):1236-1250
pubmed: 33291072
J Alzheimers Dis. 2015;46(1):35-53
pubmed: 25720414
Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):7036-41
pubmed: 20231468
Acta Neuropathol Commun. 2020 Nov 5;8(1):181
pubmed: 33153499
Psychoneuroendocrinology. 2014 Oct;48:123-35
pubmed: 24998414
Front Physiol. 2020 May 27;11:472
pubmed: 32536875
J Neurosci. 2013 Nov 13;33(46):18190-9
pubmed: 24227727
Science. 2019 Jul 19;365(6450):
pubmed: 31221773
Neurobiol Aging. 2018 Oct;70:70-77
pubmed: 30007166
Pflugers Arch. 2016 Sep;468(9):1505-16
pubmed: 27352273
Front Neurosci. 2018 Dec 11;12:930
pubmed: 30618559
Front Aging Neurosci. 2014 Sep 19;6:251
pubmed: 25285078
Neuron. 2020 Feb 5;105(3):549-561.e5
pubmed: 31810839
Brain Neurosci Adv. 2020 Oct 7;4:2398212820961725
pubmed: 33088921
J Cereb Blood Flow Metab. 2016 Sep;36(9):1481-507
pubmed: 27323783
Biochim Biophys Acta Mol Basis Dis. 2017 May;1863(5):1132-1146
pubmed: 27345267
Alzheimer Dis Assoc Disord. 2019 Jan-Mar;33(1):77-85
pubmed: 30640257
J Alzheimers Dis. 2013;35(1):179-98
pubmed: 23388174
Front Aging Neurosci. 2019 Apr 24;11:88
pubmed: 31068799
Nature. 2008 Feb 7;451(7179):720-4
pubmed: 18256671
Front Physiol. 2021 Aug 25;12:708061
pubmed: 34512381
J Neurosci. 2006 Jan 11;26(2):365-71
pubmed: 16407531
J Neuropathol Exp Neurol. 2005 Jul;64(7):588-94
pubmed: 16042310
Science. 1966 Sep 2;153(3740):1127-8
pubmed: 5918576
Psychoneuroendocrinology. 2015 Dec;62:69-79
pubmed: 26254770
Front Neurosci. 2018 Apr 20;12:196
pubmed: 29731703
J Neurochem. 2009 Jun;109(6):1636-47
pubmed: 19457117
Nat Rev Endocrinol. 2018 Oct;14(10):591-604
pubmed: 30022099
Neurobiol Dis. 2006 Dec;24(3):516-24
pubmed: 17029828
J Neurosci. 2003 Mar 15;23(6):2212-7
pubmed: 12657680
Neuron. 2014 May 21;82(4):756-71
pubmed: 24853936
Int J Mol Sci. 2017 Sep 13;18(9):
pubmed: 28902142
Physiol Behav. 2022 May 15;249:113767
pubmed: 35245527
Front Physiol. 2018 Jul 03;9:806
pubmed: 30018565
Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H647-53
pubmed: 21685266
J Biol Chem. 2016 May 27;291(22):11751-60
pubmed: 27044750
Proc Natl Acad Sci U S A. 2015 Feb 24;112(8):E881-90
pubmed: 25675483
Brain Sci. 2019 Sep 29;9(10):
pubmed: 31569571
Neuroscientist. 2021 Dec;27(6):668-684
pubmed: 33238806
Nat Rev Neurol. 2015 Aug;11(8):457-70
pubmed: 26195256
Biochem Biophys Res Commun. 2017 Jan 15;482(3):419-425
pubmed: 28212725
Neurosci Biobehav Rev. 2016 May;64:272-87
pubmed: 26969101
Nat Commun. 2018 Nov 19;9(1):4878
pubmed: 30451853
Epidemiol Rev. 2013;35:152-60
pubmed: 23314404
J Cereb Blood Flow Metab. 2021 Jan;41(1):82-91
pubmed: 31987010
Sci Rep. 2017 Jan 18;7:40753
pubmed: 28098243
J Cereb Blood Flow Metab. 2008 Oct;28(10):1652-5
pubmed: 18575459
Psychoneuroendocrinology. 2016 Mar;65:15-25
pubmed: 26708068
Diabetes Metab J. 2022 Mar;46(2):222-238
pubmed: 35299293
Neurodegener Dis. 2012;10(1-4):329-31
pubmed: 22301467
Biomedicines. 2022 Apr 27;10(5):
pubmed: 35625746
Nat Rev Neurol. 2020 Jan;16(1):30-42
pubmed: 31827267
Acta Diabetol. 2021 Jun;58(6):671-685
pubmed: 33417039
Mol Neurobiol. 2017 Aug;54(6):4696-4704
pubmed: 27443159
Diabetologia. 2022 Sep;65(9):1541-1554
pubmed: 35687178
Sci Rep. 2018 Feb 19;8(1):3269
pubmed: 29459625
Alzheimers Dement. 2022 Jan;18(1):10-28
pubmed: 34057813
Neurobiol Aging. 2004 Aug;25(7):885-92
pubmed: 15212842
J Cereb Blood Flow Metab. 2012 Jul;32(7):1277-309
pubmed: 22293983
Mol Neurobiol. 2019 Dec;56(12):8573-8588
pubmed: 31280448
Neurochem Int. 2021 Mar;144:104931
pubmed: 33276023
J Stroke. 2015 Jan;17(1):17-30
pubmed: 25692104
Diabetes. 2014 Jul;63(7):2262-72
pubmed: 24931033
Oxid Med Cell Longev. 2014;2014:360438
pubmed: 24999379
Neurochem Int. 2020 Nov;140:104818
pubmed: 32758588
BMC Neurosci. 2017 Sep 8;18(1):67
pubmed: 28886695
Adv Exp Med Biol. 2015;863:79-94
pubmed: 26092627
Front Biosci (Landmark Ed). 2022 Feb 17;27(2):71
pubmed: 35227014
Acta Neuropathol Commun. 2014 Jun 10;2:64
pubmed: 24916066