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Article ; Online: Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats.

Schrader, Joseph M / Xu, Feng / Agostinucci, Kevin J / DaSilva, Nicholas A / Van Nostrand, William E

2024 Volume 14, Issue 1, Page(s) 8441

Abstract: Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer's disease (AD). While it is known that vascular fibrillar amyloid β (Aβ) deposits leads to vascular deterioration and can drive parenchymal CAA related ...

Abstract	Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer's disease (AD). While it is known that vascular fibrillar amyloid β (Aβ) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-β1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-β1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses.
MeSH term(s)	Rats ; Animals ; Amyloid beta-Peptides/metabolism ; Transforming Growth Factor beta1/metabolism ; Proteomics ; Cerebral Amyloid Angiopathy/pathology ; Alzheimer Disease/metabolism ; Brain/metabolism ; Inflammation/pathology
Chemical Substances	Amyloid beta-Peptides ; Transforming Growth Factor beta1
Language	English
Publishing date	2024-04-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-59013-7
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Article ; Online: rTg-D: A novel transgenic rat model of cerebral amyloid angiopathy Type-2.

Davis, Judianne / Xu, Feng / Zhu, Xiaoyue / Van Nostrand, William E

Cerebral circulation - cognition and behavior

2022 Volume 3, Page(s) 100133

Abstract: Background: Cerebral amyloid angiopathy (CAA) is common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a transgenic rat model of capillary CAA type- ...

Abstract	Background: Cerebral amyloid angiopathy (CAA) is common disorder of the elderly, a prominent comorbidity of Alzheimer's disease, and causes vascular cognitive impairment and dementia. Previously, we generated a transgenic rat model of capillary CAA type-1 that develops many pathological features of human disease. However, a complementary rat model of larger vessel CAA type-2 disease has been lacking. Methods: A novel transgenic rat model (rTg-D) was generated that produces human familial CAA Dutch E22Q mutant amyloid β-protein (Aβ) in brain and develops larger vessel CAA type-2. Quantitative biochemical and pathological analyses were performed to characterize the progression of CAA and associated pathologies in aging rTg-D rats. Results: rTg-D rats begin to accumulate Aβ in brain and develop varying levels of larger vessel CAA type-2, in the absence of capillary CAA type-1, starting around 18 months of age. Larger vessel CAA was mainly composed of the Aβ40 peptide and most prominent in surface leptomeningeal/pial vessels and arterioles of the cortex and thalamus. Cerebral microbleeds and small vessel occlusions were present mostly in the thalamic region of affected rTg-D rats. In contrast to capillary CAA type-1 the amyloid deposited within the walls of larger vessels of rTg-D rats did not promote perivascular astrocyte and microglial responses or accumulate the Aβ chaperone apolipoprotein E. Conclusion: Although variable in severity, the rTg-D rats specifically develop larger vessel CAA type-2 that reflects many of the pathological features of human disease and provide a new model to investigate the pathogenesis of this condition.
Language	English
Publishing date	2022-03-11
Publishing country	Netherlands
Document type	Journal Article
ISSN	2666-2450
ISSN (online)	2666-2450
DOI	10.1016/j.cccb.2022.100133
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Article ; Online: Distinct Brain Proteomic Signatures in Cerebral Small Vessel Disease Rat Models of Hypertension and Cerebral Amyloid Angiopathy.

Schrader, Joseph M / Stanisavljevic, Aleksandra / Xu, Feng / Van Nostrand, William E

Journal of neuropathology and experimental neurology

2022 Volume 81, Issue 9, Page(s) 731–745

Abstract: Cerebral small vessel diseases (CSVDs) are prominent contributors to vascular cognitive impairment and dementia and can arise from a range of etiologies. Cerebral amyloid angiopathy (CAA) and hypertension (HTN), both prevalent in the elderly population, ... ...

Abstract	Cerebral small vessel diseases (CSVDs) are prominent contributors to vascular cognitive impairment and dementia and can arise from a range of etiologies. Cerebral amyloid angiopathy (CAA) and hypertension (HTN), both prevalent in the elderly population, lead to cerebral microhemorrhages, macrohemorrhages, and white matter damage. However, their respective underlying mechanisms and molecular events are poorly understood. Here, we show that the transgenic rat model of CAA type 1 (rTg-DI) exhibits perivascular inflammation that is lacking in the spontaneously hypertensive stroke-prone (SHR-SP) rat model of HTN. Alternatively, SHR-SP rats display notable dilation of arteriolar perivascular spaces. Comparative proteomics analysis revealed few shared altered proteins, with key proteins such as ANXA3, H2A, and HTRA1 unique to rTg-DI rats, and Nt5e, Flot-1 and Flot-2 unique to SHR-SP rats. Immunolabeling confirmed that upregulation of ANXA3, HTRA1, and neutrophil extracellular trap proteins were distinctly associated with rTg-DI rats. Pathway analysis predicted activation of TGF-β1 and TNFα in rTg-DI rat brain, while insulin signaling was reduced in the SHR-SP rat brain. Thus, we report divergent protein signatures associated with distinct cerebral vessel pathologies in the SHR-SP and rTg-DI rat models and provide new mechanistic insight into these different forms of CSVD.
MeSH term(s)	Aged ; Amyloid beta-Peptides/metabolism ; Animals ; Brain/pathology ; Cerebral Amyloid Angiopathy/etiology ; Cerebral Amyloid Angiopathy/metabolism ; Cerebral Amyloid Angiopathy/pathology ; Cerebral Small Vessel Diseases/pathology ; Disease Models, Animal ; High-Temperature Requirement A Serine Peptidase 1/metabolism ; Humans ; Hypertension/complications ; Hypertension/metabolism ; Hypertension/pathology ; Proteomics ; Rats ; Rats, Inbred SHR
Chemical Substances	Amyloid beta-Peptides ; High-Temperature Requirement A Serine Peptidase 1 (EC 3.4.21.-) ; HTRA1 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2022-07-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlac057
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Ui II Zs.134: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Ui II Zs.194: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)

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Article ; Online: An electrostatic cluster guides Aβ40 fibril formation in sporadic and Dutch-type cerebral amyloid angiopathy.

Fu, Ziao / Crooks, Elliot J / Irizarry, Brandon A / Zhu, Xiaoyue / Chowdhury, Saikat / Van Nostrand, William E / Smith, Steven O

Journal of structural biology

2024 Volume 216, Issue 2, Page(s) 108092

Abstract: Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aβ peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimer's disease (AD). We ... ...

Abstract	Cerebral amyloid angiopathy (CAA) is associated with the accumulation of fibrillar Aβ peptides upon and within the cerebral vasculature, which leads to loss of vascular integrity and contributes to disease progression in Alzheimer's disease (AD). We investigate the structure of human-derived Aβ40 fibrils obtained from patients diagnosed with sporadic or familial Dutch-type (E22Q) CAA. Using cryo-EM, two primary structures are identified containing elements that have not been observed in in vitro Aβ40 fibril structures. One population has an ordered N-terminal fold comprised of two β-strands stabilized by electrostatic interactions involving D1, E22, D23 and K28. This charged cluster is disrupted in the second population, which exhibits a disordered N-terminus and is favored in fibrils derived from the familial Dutch-type CAA patient. These results illustrate differences between human-derived CAA and AD fibrils, and how familial CAA mutations can guide fibril formation.
Language	English
Publishing date	2024-04-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	1032718-6
ISSN	1095-8657 ; 1047-8477
ISSN (online)	1095-8657
ISSN	1047-8477
DOI	10.1016/j.jsb.2024.108092
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Article ; Online: Anti-Parallel β-Hairpin Structure in Soluble Aβ Oligomers of Aβ40-Dutch and Aβ40-Iowa.

Fu, Ziao / Van Nostrand, William E / Smith, Steven O

International journal of molecular sciences

2021 Volume 22, Issue 3

Abstract: The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the ... ...

Abstract	The amyloid-β (Aβ) peptides are associated with two prominent diseases in the brain, Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). Aβ42 is the dominant component of cored parenchymal plaques associated with AD, while Aβ40 is the predominant component of vascular amyloid associated with CAA. There are familial CAA mutations at positions Glu22 and Asp23 that lead to aggressive Aβ aggregation, drive vascular amyloid deposition and result in degradation of vascular membranes. In this study, we compared the transition of the monomeric Aβ40-WT peptide into soluble oligomers and fibrils with the corresponding transitions of the Aβ40-Dutch (E22Q), Aβ40-Iowa (D23N) and Aβ40-Dutch, Iowa (E22Q, D23N) mutants. FTIR measurements show that in a fashion similar to Aβ40-WT, the familial CAA mutants form transient intermediates with anti-parallel β-structure. This structure appears before the formation of cross-β-sheet fibrils as determined by thioflavin T fluorescence and circular dichroism spectroscopy and occurs when AFM images reveal the presence of soluble oligomers and protofibrils. Although the anti-parallel β-hairpin is a common intermediate on the pathway to Aβ fibrils for the four peptides studied, the rate of conversion to cross-β-sheet fibril structure differs for each.
MeSH term(s)	Alzheimer Disease/metabolism ; Amyloid/chemistry ; Amyloid/metabolism ; Amyloid beta-Peptides/chemistry ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Benzothiazoles ; Cerebral Amyloid Angiopathy/genetics ; Cerebral Amyloid Angiopathy/metabolism ; Circular Dichroism ; Fluorescence ; Microscopy, Atomic Force ; Mutation ; Plaque, Amyloid/genetics ; Plaque, Amyloid/metabolism ; Protein Conformation, beta-Strand/genetics ; Spectroscopy, Fourier Transform Infrared
Chemical Substances	Amyloid ; Amyloid beta-Peptides ; Benzothiazoles ; thioflavin T (2390-54-7)
Language	English
Publishing date	2021-01-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22031225
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Article ; Online: Distinct brain regional proteome changes in the rTg-DI rat model of cerebral amyloid angiopathy.

Schrader, Joseph M / Xu, Feng / Van Nostrand, William E

Journal of neurochemistry

2021 Volume 159, Issue 2, Page(s) 273–291

Abstract: Cerebral amyloid angiopathy (CAA), a prevalent cerebral small vessel disease in the elderly and a common comorbidity of Alzheimer's disease, is characterized by cerebral vascular amyloid accumulation, cerebral infarction, microbleeds, and intracerebral ... ...

Abstract	Cerebral amyloid angiopathy (CAA), a prevalent cerebral small vessel disease in the elderly and a common comorbidity of Alzheimer's disease, is characterized by cerebral vascular amyloid accumulation, cerebral infarction, microbleeds, and intracerebral hemorrhages and is a prominent contributor to vascular cognitive impairment and dementia. Here, we investigate proteome changes associated with specific pathological features in several brain regions of rTg-DI rats, a preclinical model of CAA. Whereas varying degrees of microvascular amyloid and associated neuroinflammation are found in several brain regions, the presence of microbleeds and occluded small vessels is largely restricted to the thalamic region of rTg-DI rats, indicating different levels of CAA and associated pathologies occur in distinct brain regions in this model. Here, using SWATHLC-MS/MS, we report specific proteomic analysis of isolated brain regions and employ pathway analysis to correlate regionally specific proteomic changes with uniquely implicated molecular pathways. Pathway analysis suggested common activation of tumor necrosis factor α (TNFα), abnormal nervous system morphology, and neutrophil degranulation in all three regions. Activation of transforming growth factor-β1 (TGF-β1) was common to the hippocampus and thalamus, which share high CAA loads, while the thalamus, which uniquely exhibits thrombotic events, additionally displayed activation of thrombin and aggregation of blood cells. Thus, we present significant and new insight into the cerebral proteome changes found in distinct brain regions with differential CAA-related pathologies of rTg-DI rats and provide new information on potential pathogenic mechanisms associated with these regional disease processes.
MeSH term(s)	Animals ; Brain Chemistry/genetics ; Capillaries/pathology ; Cell Degranulation ; Cerebral Amyloid Angiopathy/genetics ; Computational Biology ; Disease Models, Animal ; Female ; Humans ; Male ; Mass Spectrometry ; Neutrophils/pathology ; Pathology, Molecular ; Proteome/genetics ; Proteomics ; Rats ; Rats, Transgenic ; Transforming Growth Factor beta1/genetics ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Proteome ; Tgfb1 protein, rat ; Transforming Growth Factor beta1 ; Tumor Necrosis Factor-alpha
Language	English
Publishing date	2021-08-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	80158-6
ISSN	1471-4159 ; 0022-3042 ; 1474-1644
ISSN (online)	1471-4159
ISSN	0022-3042 ; 1474-1644
DOI	10.1111/jnc.15463
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Article: Impact of Aβ40 and Aβ42 Fibrils on the Transcriptome of Primary Astrocytes and Microglia.

Zhu, Xiaoyue / Schrader, Joseph M / Irizarry, Brandon A / Smith, Steven O / Van Nostrand, William E

Biomedicines

2022 Volume 10, Issue 11

Abstract: Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer's disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ ...

Abstract	Fibrillar amyloid β-protein (Aβ) deposits in the brain, which are primarily composed of Aβ40 or Aβ42 peptides, are key pathological features of Alzheimer's disease (AD) and related disorders. Although the underlying mechanisms are still not clear, the Aβ fibrils can trigger a number of cellular responses, including activation of astrocytes and microglia. In addition, fibril structures of the Aβ40 and Aβ42 peptides are known to be polymorphic, which poses a challenge for attributing the contribution of different Aβ sequences and structures to brain pathology. Here, we systematically treated primary astrocytes and microglia with single, well-characterized polymorphs of Aβ40 or Aβ42 fibrils, and performed bulk RNA sequencing to assess cell-specific changes in gene expression. A greater number of genes were up-regulated by Aβ42 fibril-treated glial cells (251 and 2133 genes in astrocyte and microglia, respectively) compared with the Aβ40 fibril-treated glial cells (191 and 251 genes in astrocytes and microglia, respectively). Immunolabeling studies in an AD rat model with parenchymal fibrillar Aβ42 plaques confirmed the expression of
Language	English
Publishing date	2022-11-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10112982
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Article: The influence of the amyloid ß-protein and its precursor in modulating cerebral hemostasis.

Van Nostrand, William E

Biochimica et biophysica acta

2015 Volume 1862, Issue 5, Page(s) 1018–1026

Abstract: Ischemic and hemorrhagic strokes are a significant cause of brain injury leading to vascular cognitive impairment and dementia (VCID). These deleterious events largely result from disruption of cerebral hemostasis, a well-controlled and delicate balance ... ...

Abstract	Ischemic and hemorrhagic strokes are a significant cause of brain injury leading to vascular cognitive impairment and dementia (VCID). These deleterious events largely result from disruption of cerebral hemostasis, a well-controlled and delicate balance between thrombotic and fibrinolytic pathways in cerebral blood vessels and surrounding brain tissue. Ischemia and hemorrhage are both commonly associated with cerebrovascular deposition of amyloid ß-protein (Aß). In this regard, Aß directly and indirectly modulates cerebral thrombosis and fibrinolysis. Further, major isoforms of the Aß precursor protein (AßPP) function as a potent inhibitor of pro-thrombotic proteinases. The purpose of this review article is to summarize recent research on how cerebral vascular Aß and AßPP influence cerebral hemostasis. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.
MeSH term(s)	Amyloid beta-Peptides/analysis ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/analysis ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Brain/blood supply ; Brain/metabolism ; Brain/pathology ; Brain Ischemia/blood ; Brain Ischemia/metabolism ; Brain Ischemia/pathology ; Cerebral Amyloid Angiopathy/blood ; Cerebral Amyloid Angiopathy/metabolism ; Cerebral Amyloid Angiopathy/pathology ; Dementia, Vascular/blood ; Dementia, Vascular/metabolism ; Dementia, Vascular/pathology ; Hemostasis ; Humans ; Shock, Hemorrhagic/blood ; Shock, Hemorrhagic/metabolism ; Shock, Hemorrhagic/pathology
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor
Language	English
Publishing date	2015-10-27
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbadis.2015.10.020
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Article ; Online: Evaluation of Copper Chelation Therapy in a Transgenic Rat Model of Cerebral Amyloid Angiopathy.

Ambi, Ashwin / Stanisavljevic, Aleksandra / Victor, Tiffany W / Lowery, Adam W / Davis, Judianne / Van Nostrand, William E / Miller, Lisa M

ACS chemical neuroscience

2023 Volume 14, Issue 3, Page(s) 378–388

Abstract: Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of the amyloid β (Aβ) protein in blood vessels and leads to hemorrhages, strokes, and dementia in elderly individuals. Recent reports have shown elevated copper levels colocalized ... ...

Abstract	Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of the amyloid β (Aβ) protein in blood vessels and leads to hemorrhages, strokes, and dementia in elderly individuals. Recent reports have shown elevated copper levels colocalized with vascular amyloid in human CAA and Alzheimer's disease patients, which have been suggested to contribute to cytotoxicity through the formation of reactive oxygen species. Here, we treated a transgenic rat model of CAA (rTg-DI) with the copper-specific chelator, tetrathiomolybdate (TTM),
MeSH term(s)	Rats ; Humans ; Animals ; Aged ; Amyloid beta-Peptides/metabolism ; Rats, Transgenic ; Copper/metabolism ; Chelation Therapy ; Cerebral Amyloid Angiopathy/drug therapy ; Cerebral Amyloid Angiopathy/metabolism ; Alzheimer Disease/metabolism ; Animals, Wild ; Chelating Agents/pharmacology ; Chelating Agents/metabolism ; Brain/metabolism ; Plaque, Amyloid/metabolism
Chemical Substances	Amyloid beta-Peptides ; Copper (789U1901C5) ; Chelating Agents
Language	English
Publishing date	2023-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.2c00483
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Article ; Online: Cerebrospinal fluid shotgun proteomics identifies distinct proteomic patterns in cerebral amyloid angiopathy rodent models and human patients.

Vervuurt, Marc / Schrader, Joseph M / de Kort, Anna M / Kersten, Iris / Wessels, Hans J C T / Klijn, Catharina J M / Schreuder, Floris H B M / Kuiperij, H Bea / Gloerich, Jolein / Van Nostrand, William E / Verbeek, Marcel M

Acta neuropathologica communications

2024 Volume 12, Issue 1, Page(s) 6

Abstract: Cerebral amyloid angiopathy (CAA) is a form of small vessel disease characterised by the progressive deposition of amyloid β protein in the cerebral vasculature, inducing symptoms including cognitive impairment and cerebral haemorrhages. Due to their ... ...

Abstract	Cerebral amyloid angiopathy (CAA) is a form of small vessel disease characterised by the progressive deposition of amyloid β protein in the cerebral vasculature, inducing symptoms including cognitive impairment and cerebral haemorrhages. Due to their accessibility and homogeneous disease phenotypes, animal models are advantageous platforms to study diseases like CAA. Untargeted proteomics studies of CAA rat models (e.g. rTg-DI) and CAA patients provide opportunities for the identification of novel biomarkers of CAA. We performed untargeted, data-independent acquisition proteomic shotgun analyses on the cerebrospinal fluid of rTg-DI rats and wild-type (WT) littermates. Rodents were analysed at 3 months (n = 6/10), 6 months (n = 8/8), and 12 months (n = 10/10) for rTg-DI and WT respectively. For humans, proteomic analyses were performed on CSF of sporadic CAA patients (sCAA) and control participants (n = 39/28). We show recurring patterns of differentially expressed (mostly increased) proteins in the rTg-DI rats compared to wild type rats, especially of proteases of the cathepsin protein family (CTSB, CTSD, CTSS), and their main inhibitor (CST3). In sCAA patients, decreased levels of synaptic proteins (e.g. including VGF, NPTX1, NRXN2) and several members of the granin family (SCG1, SCG2, SCG3, SCG5) compared to controls were discovered. Additionally, several serine protease inhibitors of the SERPIN protein family (including SERPINA3, SERPINC1 and SERPING1) were differentially expressed compared to controls. Fifteen proteins were significantly altered in both rTg-DI rats and sCAA patients, including (amongst others) SCG5 and SERPING1. These results identify specific groups of proteins likely involved in, or affected by, pathophysiological processes involved in CAA pathology such as protease and synapse function of rTg-DI rat models and sCAA patients, and may serve as candidate biomarkers for sCAA.
MeSH term(s)	Humans ; Rats ; Animals ; Rodentia ; Complement C1 Inhibitor Protein ; Amyloid beta-Peptides ; Proteomics ; Cerebral Amyloid Angiopathy ; Endopeptidases ; Biomarkers
Chemical Substances	Complement C1 Inhibitor Protein ; Amyloid beta-Peptides ; Endopeptidases (EC 3.4.-) ; Biomarkers
Language	English
Publishing date	2024-01-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-023-01698-4
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