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000270417 1001_ $$00000-0003-4070-6756$$aİş, Özkan$$b0
000270417 245__ $$aGliovascular transcriptional perturbations in Alzheimer's disease reveal molecular mechanisms of blood brain barrier dysfunction.
000270417 260__ $$a[London]$$bNature Publishing Group UK$$c2024
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000270417 520__ $$aTo uncover molecular changes underlying blood-brain-barrier dysfunction in Alzheimer's disease, we performed single nucleus RNA sequencing in 24 Alzheimer's disease and control brains and focused on vascular and astrocyte clusters as main cell types of blood-brain-barrier gliovascular-unit. The majority of the vascular transcriptional changes were in pericytes. Of the vascular molecular targets predicted to interact with astrocytic ligands, SMAD3, upregulated in Alzheimer's disease pericytes, has the highest number of ligands including VEGFA, downregulated in Alzheimer's disease astrocytes. We validated these findings with external datasets comprising 4,730 pericyte and 150,664 astrocyte nuclei. Blood SMAD3 levels are associated with Alzheimer's disease-related neuroimaging outcomes. We determined inverse relationships between pericytic SMAD3 and astrocytic VEGFA in human iPSC and zebrafish models. Here, we detect vast transcriptome changes in Alzheimer's disease at the gliovascular-unit, prioritize perturbed pericytic SMAD3-astrocytic VEGFA interactions, and validate these in cross-species models to provide a molecular mechanism of blood-brain-barrier disintegrity in Alzheimer's disease.
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000270417 650_7 $$2NLM Chemicals$$aSmad3 Protein
000270417 650_7 $$2NLM Chemicals$$aVascular Endothelial Growth Factor A
000270417 650_7 $$2NLM Chemicals$$aSMAD3 protein, human
000270417 650_7 $$2NLM Chemicals$$aVEGFA protein, human
000270417 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000270417 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000270417 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000270417 650_2 $$2MeSH$$aHumans
000270417 650_2 $$2MeSH$$aBlood-Brain Barrier: metabolism
000270417 650_2 $$2MeSH$$aBlood-Brain Barrier: pathology
000270417 650_2 $$2MeSH$$aSmad3 Protein: metabolism
000270417 650_2 $$2MeSH$$aSmad3 Protein: genetics
000270417 650_2 $$2MeSH$$aZebrafish
000270417 650_2 $$2MeSH$$aAstrocytes: metabolism
000270417 650_2 $$2MeSH$$aVascular Endothelial Growth Factor A: metabolism
000270417 650_2 $$2MeSH$$aVascular Endothelial Growth Factor A: genetics
000270417 650_2 $$2MeSH$$aAnimals
000270417 650_2 $$2MeSH$$aPericytes: metabolism
000270417 650_2 $$2MeSH$$aPericytes: pathology
000270417 650_2 $$2MeSH$$aMale
000270417 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000270417 650_2 $$2MeSH$$aFemale
000270417 650_2 $$2MeSH$$aAged
000270417 650_2 $$2MeSH$$aTranscriptome
000270417 650_2 $$2MeSH$$aBrain: metabolism
000270417 650_2 $$2MeSH$$aBrain: pathology
000270417 650_2 $$2MeSH$$aBrain: blood supply
000270417 650_2 $$2MeSH$$aAged, 80 and over
000270417 650_2 $$2MeSH$$aDisease Models, Animal
000270417 7001_ $$00000-0003-1964-4124$$aWang, Xue$$b1
000270417 7001_ $$00000-0002-1783-4453$$aReddy, Joseph S$$b2
000270417 7001_ $$00000-0001-8775-8743$$aMin, Yuhao$$b3
000270417 7001_ $$00000-0001-7045-5068$$aYilmaz, Elanur$$b4
000270417 7001_ $$0P:(DE-2719)2811306$$aBhattarai, Prabesh$$b5$$udzne
000270417 7001_ $$aPatel, Tulsi$$b6
000270417 7001_ $$aBergman, Jeremiah$$b7
000270417 7001_ $$00000-0002-8791-0925$$aQuicksall, Zachary$$b8
000270417 7001_ $$aHeckman, Michael G$$b9
000270417 7001_ $$aTutor-New, Frederick Q$$b10
000270417 7001_ $$00000-0002-1536-6123$$aCan Demirdogen, Birsen$$b11
000270417 7001_ $$aWhite, Launia$$b12
000270417 7001_ $$00000-0001-8868-9700$$aKoga, Shunsuke$$b13
000270417 7001_ $$aKrause, Vincent$$b14
000270417 7001_ $$aInoue, Yasuteru$$b15
000270417 7001_ $$00000-0001-6751-9374$$aKanekiyo, Takahisa$$b16
000270417 7001_ $$0P:(DE-2719)2811286$$aCosacak, Mehmet Ilyas$$b17
000270417 7001_ $$aNelson, Nastasia$$b18
000270417 7001_ $$aLee, Annie J$$b19
000270417 7001_ $$00000-0002-5560-4085$$aVardarajan, Badri$$b20
000270417 7001_ $$aMayeux, Richard$$b21
000270417 7001_ $$00000-0002-6841-9882$$aKouri, Naomi$$b22
000270417 7001_ $$00000-0002-5496-0598$$aDeniz, Kaancan$$b23
000270417 7001_ $$aCarnwath, Troy$$b24
000270417 7001_ $$aOatman, Stephanie R$$b25
000270417 7001_ $$00000-0002-6013-8322$$aLewis-Tuffin, Laura J$$b26
000270417 7001_ $$00000-0001-8879-7090$$aNguyen, Thuy$$b27
000270417 7001_ $$aInitiative, Alzheimer’s Disease Neuroimaging$$b28$$eCollaboration Author
000270417 7001_ $$00000-0002-3231-9134$$aCarrasquillo, Minerva M$$b29
000270417 7001_ $$aGraff-Radford, Jonathan$$b30
000270417 7001_ $$00000-0002-8178-6601$$aPetersen, Ronald C$$b31
000270417 7001_ $$00000-0001-7916-622X$$aJr Jack, Clifford R$$b32
000270417 7001_ $$aKantarci, Kejal$$b33
000270417 7001_ $$00000-0001-7379-2545$$aMurray, Melissa E$$b34
000270417 7001_ $$aNho, Kwangsik$$b35
000270417 7001_ $$00000-0002-1376-8532$$aSaykin, Andrew J$$b36
000270417 7001_ $$00000-0001-7189-7917$$aDickson, Dennis W$$b37
000270417 7001_ $$0P:(DE-2719)2811030$$aKizil, Caghan$$b38$$udzne
000270417 7001_ $$00000-0002-2685-427X$$aAllen, Mariet$$b39
000270417 7001_ $$00000-0003-4436-8889$$aErtekin-Taner, Nilüfer$$b40
000270417 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-024-48926-6$$gVol. 15, no. 1, p. 4758$$n1$$p4758$$tNature Communications$$v15$$x2041-1723$$y2024
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