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

Mendonça, Clarissa Ferolla LU ; Kuras, Magdalena LU orcid ; Nogueira, Fábio César Sousa LU ; Plá, Indira LU orcid ; Hortobágyi, Tibor ; Csiba, László ; Palkovits, Miklós ; Renner, Éva ; Döme, Péter and Marko-Varga, György LU , et al. (2019) In Neurobiology of Disease 130.
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... (More)

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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Contribution to journal
publication status
published
subject
keywords
Alzheimer's disease, Braak/Braak staging, Brain region vulnerability, Medial temporal lobe, Neocortex, Proteomics
in
Neurobiology of Disease
volume
130
article number
104509
publisher
Elsevier
external identifiers
  • scopus:85067554418
  • pmid:31207390
ISSN
0969-9961
DOI
10.1016/j.nbd.2019.104509
language
English
LU publication?
yes
id
30e6dc56-4798-428c-928d-a2ba91b0c6e6
date added to LUP
2019-07-04 13:13:07
date last changed
2024-02-15 16:18:53
@article{30e6dc56-4798-428c-928d-a2ba91b0c6e6,
  abstract     = {{<p>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.</p>}},
  author       = {{Mendonça, Clarissa Ferolla and Kuras, Magdalena and Nogueira, Fábio César Sousa and Plá, Indira and Hortobágyi, Tibor and Csiba, László and Palkovits, Miklós and Renner, Éva and Döme, Péter and Marko-Varga, György and Domont, Gilberto B. and Rezeli, Melinda}},
  issn         = {{0969-9961}},
  keywords     = {{Alzheimer's disease; Braak/Braak staging; Brain region vulnerability; Medial temporal lobe; Neocortex; Proteomics}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Neurobiology of Disease}},
  title        = {{Proteomic signatures of brain regions affected by tau pathology in early and late stages of Alzheimer's disease}},
  url          = {{http://dx.doi.org/10.1016/j.nbd.2019.104509}},
  doi          = {{10.1016/j.nbd.2019.104509}},
  volume       = {{130}},
  year         = {{2019}},
}