Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease

Clarissa Ferolla Mendonça, Magdalena Kuras, Fábio César Sousa Nogueira, Indira Plá, T. Hortobágyi, L. Csiba, M. Palkóvits, Éva Renner, P. Döme, György Marko-Varga, Gilberto B. Domont, Melinda Rezeli

Research output: Contribution to journalArticle

Abstract

Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder. Depositions of amyloid β peptide (Aβ) and tau protein are among the major pathological hallmarks of AD. Aβ and tau burden follows predictable spatial patterns during the progression of AD. Nevertheless, it remains obscure why certain brain regions are more vulnerable than others; to investigate this and dysregulated pathways during AD progression, a mass spectrometry-based proteomics study was performed. Methods: In total 103 tissue samples from regions early (entorhinal and parahippocampal cortices - medial temporal lobe (MTL)) and late affected (temporal and frontal cortices - neocortex) by tau pathology were subjected to label-free quantitative proteomics analysis. Results: Considering dysregulated proteins during AD progression, the majority (625 out of 737 proteins) was region specific, while some proteins were shared between regions (101 proteins altered in two areas and 11 proteins altered in three areas). Analogously, many dysregulated pathways during disease progression were exclusive to certain regions, but a few pathways altered in two or more areas. Changes in protein expression indicate that synapse loss occurred in all analyzed regions, while translation dysregulation was preponderant in entorhinal, parahippocampal and frontal cortices. Oxidative phosphorylation impairment was prominent in MTL. Differential proteomic analysis of brain areas in health state (controls) showed higher metabolism and increased expression of AD-related proteins in the MTL compared to the neocortex. In addition, several proteins that differentiate brain regions in control tissue were dysregulated in AD. Conclusions: This work provides the comparison of proteomic changes in brain regions affected by tau pathology at different stages of AD. Although we identified commonly regulated proteins and pathways during disease advancement, we found that the dysregulated processes are predominantly region specific. In addition, a distinct proteomic signature was found between MTL and neocortex in healthy subjects that might be related to AD vulnerability. These findings highlight the need for investigating AD's cascade of events throughout the whole brain and studies spanning more brain areas are required to better understand AD etiology and region vulnerability to disease.

Original languageEnglish
Article number104509
JournalNeurobiology of Disease
Volume130
DOIs
Publication statusPublished - Oct 1 2019

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Proteomics
Alzheimer Disease
Pathology
Brain
Temporal Lobe
Proteins
Neocortex
Disease Progression
Entorhinal Cortex
Frontal Lobe
Serum Amyloid A Protein
tau Proteins
Oxidative Phosphorylation
Neurodegenerative Diseases
Synapses
Mass Spectrometry
Healthy Volunteers
Health

Keywords

  • Alzheimer's disease
  • Braak/Braak staging
  • Brain region vulnerability
  • Medial temporal lobe
  • Neocortex
  • Proteomics

ASJC Scopus subject areas

  • Neurology

Cite this

Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease. / Mendonça, Clarissa Ferolla; Kuras, Magdalena; Nogueira, Fábio César Sousa; Plá, Indira; Hortobágyi, T.; Csiba, L.; Palkóvits, M.; Renner, Éva; Döme, P.; Marko-Varga, György; Domont, Gilberto B.; Rezeli, Melinda.

In: Neurobiology of Disease, Vol. 130, 104509, 01.10.2019.

Research output: Contribution to journalArticle

Mendonça, Clarissa Ferolla ; Kuras, Magdalena ; Nogueira, Fábio César Sousa ; Plá, Indira ; Hortobágyi, T. ; Csiba, L. ; Palkóvits, M. ; Renner, Éva ; Döme, P. ; Marko-Varga, György ; Domont, Gilberto B. ; Rezeli, Melinda. / Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease. In: Neurobiology of Disease. 2019 ; Vol. 130.
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AU - Kuras, Magdalena

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AU - Plá, Indira

AU - Hortobágyi, T.

AU - Csiba, L.

AU - Palkóvits, M.

AU - Renner, Éva

AU - Döme, P.

AU - Marko-Varga, György

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N2 - Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder. Depositions of amyloid β peptide (Aβ) and tau protein are among the major pathological hallmarks of AD. Aβ and tau burden follows predictable spatial patterns during the progression of AD. Nevertheless, it remains obscure why certain brain regions are more vulnerable than others; to investigate this and dysregulated pathways during AD progression, a mass spectrometry-based proteomics study was performed. Methods: In total 103 tissue samples from regions early (entorhinal and parahippocampal cortices - medial temporal lobe (MTL)) and late affected (temporal and frontal cortices - neocortex) by tau pathology were subjected to label-free quantitative proteomics analysis. Results: Considering dysregulated proteins during AD progression, the majority (625 out of 737 proteins) was region specific, while some proteins were shared between regions (101 proteins altered in two areas and 11 proteins altered in three areas). Analogously, many dysregulated pathways during disease progression were exclusive to certain regions, but a few pathways altered in two or more areas. Changes in protein expression indicate that synapse loss occurred in all analyzed regions, while translation dysregulation was preponderant in entorhinal, parahippocampal and frontal cortices. Oxidative phosphorylation impairment was prominent in MTL. Differential proteomic analysis of brain areas in health state (controls) showed higher metabolism and increased expression of AD-related proteins in the MTL compared to the neocortex. In addition, several proteins that differentiate brain regions in control tissue were dysregulated in AD. Conclusions: This work provides the comparison of proteomic changes in brain regions affected by tau pathology at different stages of AD. Although we identified commonly regulated proteins and pathways during disease advancement, we found that the dysregulated processes are predominantly region specific. In addition, a distinct proteomic signature was found between MTL and neocortex in healthy subjects that might be related to AD vulnerability. These findings highlight the need for investigating AD's cascade of events throughout the whole brain and studies spanning more brain areas are required to better understand AD etiology and region vulnerability to disease.

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