Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. CVD is known to increase the risk of subsequent neurodegeneration but the mechanism(s) and proteins involved have yet to be elucidated.

We previously showed that myocardial infarction (MI), induced in mice and compared to sham-MI mice, leads to increases in protein aggregation, endoplasmic reticulum (ER) stress in both heart and brain, and changes in proteostatic pathways.

In this study, we further investigate the molecular mechanisms altered by induced MI in mice, which were also implicated by proteomics of postmortem human hippocampal aggregates from Alzheimer's disease (AD) and cardiovascular disease (CVD) patients, vs. age-matched controls (AMC).

We utilized intra-aggregate crosslinking to identify protein-protein contacts or proximities, and thus to reconstruct aggregate "contactomes" (nonfunctional interactomes).

We used leave-one-out analysis (LOOA) to determine the contribution of each protein to overall aggregate cohesion, and gene ontology meta-analyses of constituent proteins to define critical organelles, processes, and pathways that distinguish AD and/or CVD from AMC aggregates.

We identified influential proteins in both AD and CVD aggregates, many of which are associated with pathways or processes previously implicated in neurodegeneration such as mitochondrial, oxidative, and endoplasmic-reticulum stress; protein aggregation and proteostasis; the ubiquitin proteasome system and autophagy; axonal transport; and synapses.

COI Statement

Declarations. Conflict of interest: The authors declare that they have no conflict of interest. Ethical approval: The research presented here was reviewed by the Institutional Review Board of the Central Arkansas Veterans Healthcare System (CAVHS IRB), which deemed it non-human-subject research due to our use of de-identified brain tissue from an approved brain bank, plus mechanistic studies of cultured human cell lines model of AD-like aggregation.

References:

Adesuyan M, Jani YH, Alsugeir D, Howard R, Wong ICK, Wei L, Brauer R (2023) Trends in the incidence of dementia in people with hypertension in the UK 2000 to 2021. Alzheimers Dement (Amst) 15:e12466. https://doi.org/10.1002/dad2.12466
Ayyadevara S, Balasubramaniam M, Parcon PA, Barger SW, Griffin WS, Alla R, Tackett AJ, Mackintosh SG, Petricoin E, Zhou W, Shmookler Reis RJ (2016) Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer’s hippocampus from normal controls. Aging Cell 15:924–939. https://doi.org/10.1111/acel.12501
Ayyadevara S, Ganne A, Balasubramaniam M, Shmookler Reis RJ (2022) Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration. Metab Brain Dis 37:147–152. https://doi.org/10.1007/s11011-021-00791-8
Ayyadevara S, Mercanti F, Wang X, Mackintosh SG, Tackett AJ, Prayaga SV, Romeo F, Shmookler Reis RJ, Mehta JL (2016) Age- and hypertension-associated protein aggregates in mouse heart have similar proteomic profiles. Hypertension 67:1006–1013. https://doi.org/10.1161/hypertensionaha.115.06849
Balasubramaniam M, Ayyadevara S, Ganne A, Kakraba S, Penthala NR, Du X, Crooks PA, Griffin ST, Shmookler Reis RJ (2019) Aggregate interactome based on protein cross-linking interfaces predicts drug targets to limit aggregation in neurodegenerative diseases. iScience 20:248–264. https://doi.org/10.1016/j.isci.2019.09.026

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Doi:

10.1007/s00395-025-01109-w

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Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.

Abstract

We utilized intra-aggregate crosslinking to identify protein-protein contacts or proximities, and thus to reconstruct aggregate "contactomes" (nonfunctional interactomes).

COI Statement

References:

Adesuyan M, Jani YH, Alsugeir D, Howard R, Wong ICK, Wei L, Brauer R (2023) Trends in the incidence of dementia in people with hypertension in the UK 2000 to 2021. Alzheimers Dement (Amst) 15:e12466. https://doi.org/10.1002/dad2.12466
Ayyadevara S, Balasubramaniam M, Parcon PA, Barger SW, Griffin WS, Alla R, Tackett AJ, Mackintosh SG, Petricoin E, Zhou W, Shmookler Reis RJ (2016) Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer’s hippocampus from normal controls. Aging Cell 15:924–939. https://doi.org/10.1111/acel.12501
Ayyadevara S, Ganne A, Balasubramaniam M, Shmookler Reis RJ (2022) Intrinsically disordered proteins identified in the aggregate proteome serve as biomarkers of neurodegeneration. Metab Brain Dis 37:147–152. https://doi.org/10.1007/s11011-021-00791-8
Ayyadevara S, Mercanti F, Wang X, Mackintosh SG, Tackett AJ, Prayaga SV, Romeo F, Shmookler Reis RJ, Mehta JL (2016) Age- and hypertension-associated protein aggregates in mouse heart have similar proteomic profiles. Hypertension 67:1006–1013. https://doi.org/10.1161/hypertensionaha.115.06849
Balasubramaniam M, Ayyadevara S, Ganne A, Kakraba S, Penthala NR, Du X, Crooks PA, Griffin ST, Shmookler Reis RJ (2019) Aggregate interactome based on protein cross-linking interfaces predicts drug targets to limit aggregation in neurodegenerative diseases. iScience 20:248–264. https://doi.org/10.1016/j.isci.2019.09.026

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Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.

Abstract

COI Statement

References:

Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.

Abstract

COI Statement

References: