Proteomic Changes in the Human Cerebrovasculature in Alzheimer’s Disease and Related Tauopathies Linked to Peripheral Biomarkers in Plasma and Cerebrospinal Fluid

Wojtas, Aleksandra M.; Dammer, Eric B.; Guo, Qi; Ping, Lingyan; Shantaraman, Ananth; Duong, Duc M.; Yin, Luming; Fox, Edward J.; Seifar, Fatemeh; Lee, Edward B.; Johnson, Erik C. B.; Lah, James J.; Levey, Allan I.; Levites, Yona; Rangaraju, Srikant; Golde, Todd E.; Seyfried, Nicholas T.

doi:10.1101/2024.01.10.24301099

Cited by 3 publications

References 86 publications

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Differences in the cerebral amyloid angiopathy proteome in Alzheimer’s disease and mild cognitive impairment

Leitner,

Kavanagh,

Kanshin

et al. 2024

Acta Neuropathol

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Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta (Aβ) deposition in cerebrovasculature. It is prevalent with aging and Alzheimer’s disease (AD), associated with intracerebral hemorrhage, and contributes to cognitive deficits. To better understand molecular mechanisms, CAA(+) and CAA(−) vessels were microdissected from paraffin-embedded autopsy temporal cortex of age-matched Control (n = 10), mild cognitive impairment (MCI; n = 4), and sporadic AD (n = 6) cases, followed by label-free quantitative mass spectrometry. 257 proteins were differentially abundant in CAA(+) vessels compared to neighboring CAA(−) vessels in MCI, and 289 in AD (p < 0.05, fold-change > 1.5). 84 proteins changed in the same direction in both groups, and many changed in the same direction among proteins significant in at least one group (p < 0.0001, R2 = 0.62). In CAA(+) vessels, proteins significantly increased in both AD and MCI were particularly associated with collagen-containing extracellular matrix, while proteins associated with ribonucleoprotein complex were significantly decreased in both AD and MCI. In neighboring CAA(−) vessels, 61 proteins were differentially abundant in MCI, and 112 in AD when compared to Control cases. Increased proteins in CAA(−) vessels were associated with extracellular matrix, external encapsulating structure, and collagen-containing extracellular matrix in MCI; collagen trimer in AD. Twenty two proteins were increased in CAA(−) vessels of both AD and MCI. Comparison of the CAA proteome with published amyloid-plaque proteomic datasets identified many proteins similarly enriched in CAA and plaques, as well as a protein subset hypothesized as preferentially enriched in CAA when compared to plaques. SEMA3G emerged as a CAA specific marker, validated immunohistochemically and with correlation to pathology levels (p < 0.0001; R2 = 0.90). Overall, the CAA(−) vessel proteomes indicated changes in vessel integrity in AD and MCI in the absence of Aβ, and the CAA(+) vessel proteome was similar in MCI and AD, which was associated with vascular matrix reorganization, protein translation deficits, and blood brain barrier breakdown.

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Differences in the cerebral amyloid angiopathy proteome in Alzheimer’s disease and mild cognitive impairment

Leitner,

Kavanagh,

Kanshin

et al. 2024

Acta Neuropathol

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Network Analysis of the Cerebrospinal Fluid Proteome Reveals Shared and Unique Differences Between Sporadic and Familial Forms of Amyotrophic Lateral Sclerosis

Trautwig,

Fox,

Dammer

et al. 2024

Preprint

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BackgroundAmyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3-5 years of disease onset. Although roughly 10 % of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause of the majority of cases is unknown. Consequently, there is a critical need for biomarkers that reflect disease onset and progression across ALS subgroups.MethodsWe employed tandem mass tag mass spectrometry (TMT-MS) based proteomics on cerebrospinal fluid (CSF) to identify and quantify 2105 proteins from ALS patients with sporadic disease (n=35), C9orf72 ALS (n=10), and SOD1 ALS (n=6), as well as age-matched healthy controls (n=44) and asymptomatic C9orf72 carriers (n=6). We used differential protein abundance and network analyses to determine how protein profiles vary across disease types in ALS CSF.ResultsIntegrated differential and co-expression network analysis identified proteomic differences between ALS and control, and differentially abundant proteins between sporadic, C9orf72 and SOD1 ALS. Groups of proteins also differentiated asymptomatic C9orf72 mutation carriers from those with C9orf72 ALS, marking a pre-symptomatic proteomic signature of C9orf72 ALS. Similarly, additional proteins differentiated asymptomatic from controls. Leveraging additional publicly available ALS and AD proteomic datasets, we validated our ALS CSF network and identified ALS-specific proteins within Module 5 (M5)-Extracellular matrix (e.g., IGF2, RARRES2, LGALS3, GALNT15, and LYZ) and shared biomarkers across neurodegenerative diseases linked to Module 10 (M10)-Ubiquitination/Gluconeogenesis (e.g., NEFL, NEFM, CHIT1, and CHI3L1).ConclusionsThis study represents a comprehensive analysis of the CSF proteome across sporadic and genetic causes of ALS that resolves differences among these disease subgroups and points to varying pathogenic pathways that result in disease.

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Large-scale Deep Proteomic Analysis in Alzheimer’s Disease Brain Regions Across Race and Ethnicity

Seifar,

Fox,

Shantaraman

et al. 2024

Preprint

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Introduction Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, yet our comprehension predominantly relies on studies within the non-Hispanic White (NHW) population. Here we aimed to provide comprehensive insights into the proteomic landscape of AD across diverse racial and ethnic groups. Methods Dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) brain tissues were donated from multiple centers (Mayo Clinic, Emory University, Rush University, Mt. Sinai School of Medicine) and were harmonized through neuropathological evaluation, specifically adhering to the Braak staging and CERAD criteria. Among 1105 DLPFC tissue samples (998 unique individuals), 333 were from African American donors, 223 from Latino Americans, 529 from NHW donors, and the rest were from a mixed or unknown racial background. Among 280 STG tissue samples (244 unique individuals), 86 were African American, 76 Latino American, 116 NHW and the rest were mixed or unknown ethnicity. All tissues were uniformly homogenized and analyzed by tandem mass tag mass spectrometry (TMT-MS). Results As a Quality control (QC) measure, proteins with more than 50% missing values were removed and iterative principal component analysis was conducted to remove outliers within brain regions. After QC, 9,180 and 9,734 proteins remained in the DLPC and STG proteome, respectively, of which approximately 9,000 proteins were shared between regions. Protein levels of microtubule-associated protein tau (MAPT) and amyloid-precursor protein (APP) demonstrated AD-related elevations in DLPFC tissues with a strong association with CERAD and Braak across racial groups. APOE4 protein levels in brain were highly concordant with APOE genotype of the individuals. Discussion This comprehensive region resolved large-scale proteomic dataset provides a resource for the understanding of ethnoracial-specific protein differences in AD brain.

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Proteomic Changes in the Human Cerebrovasculature in Alzheimer’s Disease and Related Tauopathies Linked to Peripheral Biomarkers in Plasma and Cerebrospinal Fluid

Cited by 3 publications

References 86 publications

Differences in the cerebral amyloid angiopathy proteome in Alzheimer’s disease and mild cognitive impairment

Differences in the cerebral amyloid angiopathy proteome in Alzheimer’s disease and mild cognitive impairment

Network Analysis of the Cerebrospinal Fluid Proteome Reveals Shared and Unique Differences Between Sporadic and Familial Forms of Amyotrophic Lateral Sclerosis

Large-scale Deep Proteomic Analysis in Alzheimer’s Disease Brain Regions Across Race and Ethnicity

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