Dataset Information

Cardiac Amyloid Tissue Proteome

ABSTRACT: Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction, mostly because these remain unknown. Our prior work has focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations. In this study, we used a bulk (entire biopsy) tissue proteomics approach to evaluate mechanisms of tissue dysfunction in cardiac AL/ATTR. We included 76 ATTR cases and 27 AL cases. In stage 3 AL patients, pathways involved in coagulation, extracellular matrix (ECM) remodeling, epithelial-to-mesenchymal transition (EMT), complement activation, hypoxia and clathrin-mediated endocytosis were increased compared to stage 1/2,whereas pathways involved in healthy cardiac metabolism and proteostasis were decreased. In Mayo stage 2/3 ATTR, immunoglobulin proteins, complement and keratin pathways were increased compared to stage 1. Principal component analyses identified an ATTR group with worse survival independent of existing staging systems that also showed upregulation of complement and downregulation of oxidative phosphorylation pathways. Finally, when comparing AL with ATTR, complement proteins were increased in ATTR whereas clathrin-mediated endocytosis , mRNA splicing, spliceosome pathways and ribosomal proteins were increased in AL. Clathrin-mediated endocytosis has been implicated in Aβ amyloid clearance by non-immune cells in the setting of Alzheimer’s disease and could represent a proteostatic mechanism of cardiomyocytes in response to AL fibrils. Impaired spliceosome and translation machinery has been associated with cardiac ECM-R in other cardiomyopathies. Our results support an immune-mediated mechanism of tissue toxicity in cardiac amyloidosis including activation of the complement cascade, especially among ATTR patients with worse outcomes.

INSTRUMENT(S): maXis

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart

SUBMITTER: Surendra Dasari

LAB HEAD: Surendra Dasari

PROVIDER: PXD058715 | Pride | 2025-01-15

REPOSITORIES: pride

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			Action	DRS
	P23001_158samp_kj6_Report_2.xls.xlsx	Xlsx
	P23001_230412_06_T050_BA1_1_4105.d.tar	Other
	P23001_230412_08_T051_BA2_1_4107.d.tar	Other
	P23001_230412_10_L005_BA3_1_4109.d.tar	Other
	P23001_230412_12_T067_BA4_1_4111.d.tar	Other

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Publications

Whole tissue proteomic analyses of cardiac ATTR and AL unveil mechanisms of tissue damage.

Netzel Brian C BC Charlesworth M Cristine MC Johnson Kenneth L KL French Amy J AJ Dispenzieri Angela A Maleszewski Joseph J JJ McPhail Ellen D ED Grogan Martha M Redfield Margaret M MM Weivoda Megan M Muchtar Eli E Gertz Morie A MA Kumar Shaji K SK Misra Pinaki P Vrana Julie J Theis Jason J Hayman Suzanne R SR Ramirez-Alvarado Marina M Dasari Surendra S Kourelis Taxiarchis T

Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 20250108 1

<h4>Background</h4>Cardiac AL and ATTR are potentially fatal cardiomyopathies. Current therapies do not address mechanisms of tissue dysfunction because these remain unknown. Our prior work focused on the amyloid plaque proteome, which may not capture tissue-wide proteomic alterations.<h4>Objectives</h4>To evaluate mechanisms of tissue dysfunction in cardiac AL and ATTR using a full biopsy tissue proteomics approach.<h4>Methods</h4>We performed proteomics analysis on 76 ATTR and 27 AL diagnostic ...[more]

PMID: 39773246

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Project description:The purpose of this study was to determine whether there were differences in gene expression in the hippocampus, a part of the brain involved in memory consolidation, between male mice with age-related memory deficits (SAMP8 mice) and control mice with no age-related memory deficits. The senescence-accelerated mouse (SAMP8) strain exhibits decreased learning and memory and increased amyloid beta peptide (Aβ) accumulation at 12 months compared to 4 months. To detect differences in gene expression in SAMP8 mice, we used a Control mouse that was a 50% cross between SAMP8 and CD-1 mice and which showed no memory deficits (50% SAMP8 mouse). We then compared gene expression in the hippocampus of 4 month and 12 month old SAMP8 and Control mice using Affymetrix gene arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the Long Term Potentiation (LTP) (6 genes), Phosphatidylinositol Signaling (6 genes), and Endocytosis (10 genes) pathways. The changes in LTP included MAPK signaling (N-ras, CREB binding protein, protein phosphatase inhibitor 1) and Ca-dependent signaling (PI receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through PI3-kinase, and Western blotting revealed phosphorylation changes in AKT and 70S6K. Changes in the Endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered genes expression in three SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways may provide new therapeutic targets in addition to targeting Aβ metabolism itself. Global differential profiling of hippocampal gene expression (4 month and 12 month old SAMP8 and Control mice) was performed using Affymetrix GeneChip® Mouse Genome 430 2.0 Arrays. At 12 months, but not at 4 months, pathway analysis revealed significant differences in the Long Term Potentiation (LTP) (6 genes), Phosphatidylinositol Signaling (6 genes), and Endocytosis (10 genes) pathways. The changes in LTP included MAPK signaling (N-ras, CREB binding protein, protein phosphatase inhibitor 1) and Ca-dependent signaling (PI receptors 1 and 2 and phospholipase C). Changes in phosphatidylinositol signaling genes suggested altered signaling through PI3-kinase, and Western blotting revealed phosphorylation changes in AKT and 70S6K. Changes in the Endocytosis pathway involved genes related to clathrin-mediated endocytosis (dynamin and clathrin). Endocytosis is required for receptor recycling, is involved in Aβ metabolism, and is regulated by phosphatidylinositol signaling. In summary, these studies demonstrate altered genes expression in three SAMP8 hippocampal pathways associated with memory formation and consolidation. These pathways may provide new therapeutic targets in addition to targeting Aβ metabolism itself. 2-way ANOVA (2 x 2 conditions, n=4). First variable was age (4 and 12 months) and second variable was mouse strain (Control and SAMP8). This results in 4 groups: Control-4 month, Control-12 month, SAMP8-4 month, and SAMP8-12 month. Each group had 4 biological replicates (4 mice). The ”Control” mice were a 50% backcross of the SAMP8 mice with CD-1 mice (50% SAMP8 mice). These mice were closely related to SAMP8 mice but exhibited no memory deficits at 4 or 12 months. The SAMP8 mice had memory deficits at 12 months but not at 4 months.