Modifications of the endosomal compartment in fibroblasts from sporadic Alzheimer's disease patients are associated with cognitive impairment.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
14 02 2023
14 02 2023
Historique:
received:
23
02
2022
accepted:
03
02
2023
revised:
31
01
2023
entrez:
14
2
2023
pubmed:
15
2
2023
medline:
17
2
2023
Statut:
epublish
Résumé
Morphological alterations of the endosomal compartment have been widely described in post-mortem brains from Alzheimer's disease (AD) patients and subjects with Down syndrome (DS) who are at high risk for AD. Immunostaining with antibodies against endosomal markers such as Early Endosome Antigen 1 (EEA1) revealed increased size of EEA1-positive puncta. In DS, peripheral cells such as peripheral blood mononuclear cells (PBMCs) and fibroblasts, share similar phenotype even in the absence of AD. We previously found that PBMCs from AD patients have larger EEA1-positive puncta, correlating with brain amyloid load. Here we analysed the endosomal compartment of fibroblasts from a very well characterised cohort of AD patients (IMABio3) who underwent thorough clinical, imaging and biomarkers assessments. Twenty-one subjects were included (7 AD with mild cognitive impairment (AD-MCI), 7 AD with dementia (AD-D) and 7 controls) who had amyloid-PET at baseline (PiB) and neuropsychological tests at baseline and close to skin biopsy. Fibroblasts isolated from skin biopsies were immunostained with anti-EEA1 antibody and imaged using a spinning disk microscope. Endosomal compartment ultrastructure was also analysed by electron microscopy. All fibroblast lines were genotyped and their AD risk factors identified. Our results show a trend to an increased EEA1-positive puncta volume in fibroblasts from AD-D as compared to controls (p.adj = 0.12) and reveal enhanced endosome area in fibroblasts from AD-MCI and AD-AD versus controls. Larger puncta size correlated with PiB retention in different brain areas and with worse cognitive scores at the time of biopsy as well as faster decline from baseline to the time of biopsy. Finally, we identified three genetic risk factors for AD (ABCA1, COX7C and MYO15A) that were associated with larger EEA1 puncta volume. In conclusion, the endosomal compartment in fibroblasts could be used as cellular peripheral biomarker for both amyloid deposition and cognitive decline in AD patients.
Identifiants
pubmed: 36788216
doi: 10.1038/s41398-023-02355-z
pii: 10.1038/s41398-023-02355-z
pmc: PMC9929231
doi:
Substances chimiques
Amyloid
0
Amyloid beta-Peptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
54Informations de copyright
© 2023. The Author(s).
Références
Acta Neuropathol Commun. 2021 Apr 14;9(1):70
pubmed: 33853668
Nat Genet. 2016 Oct;48(10):1279-83
pubmed: 27548312
Neurobiol Aging. 2012 Jul;33(7):1253-7
pubmed: 21489655
Nat Rev Neurosci. 2007 Jul;8(7):499-509
pubmed: 17551515
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Front Neurosci. 2017 Dec 12;11:702
pubmed: 29311783
Lancet Neurol. 2010 Nov;9(11):1118-27
pubmed: 20934914
Mol Psychiatry. 2016 May;21(5):707-16
pubmed: 26194181
J Biol Chem. 2003 Aug 15;278(33):31261-8
pubmed: 12761223
Cell Rep. 2020 Nov 24;33(8):108420
pubmed: 33238112
Neurology. 2007 Nov 6;69(19):1859-67
pubmed: 17984454
Arch Gen Psychiatry. 2006 Feb;63(2):168-74
pubmed: 16461860
Nat Genet. 2022 Apr;54(4):412-436
pubmed: 35379992
Curr Opin Cell Biol. 2022 Dec;79:102132
pubmed: 36257241
Am J Pathol. 2000 Jul;157(1):277-86
pubmed: 10880397
Neuromolecular Med. 2014 Mar;16(1):150-60
pubmed: 24101586
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
Curr Genomics. 2018 May;19(4):279-288
pubmed: 29755290
Cell Death Dis. 2018 Mar 7;9(3):385
pubmed: 29515184
Proc Natl Acad Sci U S A. 2018 Jul 10;115(28):E6640-E6649
pubmed: 29946028
Nature. 2012 Jan 25;482(7384):216-20
pubmed: 22278060
J Cell Sci. 2021 Jun 1;134(11):
pubmed: 34096603
Acta Neuropathol Commun. 2021 Feb 12;9(1):25
pubmed: 33579389
Neurobiol Aging. 2004 Nov-Dec;25(10):1263-72
pubmed: 15465622
J Neurosci. 1996 Jan;16(1):186-99
pubmed: 8613784
Alzheimers Res Ther. 2019 Sep 14;11(1):82
pubmed: 31521194
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Brain. 2018 Jun 1;141(6):1855-1870
pubmed: 29608645
Acta Neuropathol Commun. 2020 Jun 24;8(1):89
pubmed: 32580751
Transl Psychiatry. 2015 Jul 07;5:e595
pubmed: 26151923
J Neurosci. 1997 Aug 15;17(16):6142-51
pubmed: 9236226
Cold Spring Harb Perspect Med. 2012 May;2(5):a006270
pubmed: 22553493
Nature. 2020 Feb;578(7795):419-424
pubmed: 31996848
Nature. 2021 Feb;590(7845):290-299
pubmed: 33568819
Front Mol Neurosci. 2021 Jan 22;13:583755
pubmed: 33551742
Hum Mol Genet. 2012 Jul 15;21(14):3156-72
pubmed: 22511594
Am J Pathol. 2008 Aug;173(2):370-84
pubmed: 18535180
J Biol Chem. 2004 Apr 9;279(15):15571-8
pubmed: 14747463
Neurobiol Aging. 2017 May;53:36-47
pubmed: 28208064