uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Altered proteins in the aging brain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
Show others and affiliations
2016 (English)In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 75, no 4, 316-325 p.Article in journal (Refereed) Published
Abstract [en]

We assessed the prevalence of common altered brain proteins in 296 cognitively unimpaired subjects ranging from age 50 to 102 years. The incidence and the stage of hyperphosphorylated-tau (HP tau), beta-amyloid, alpha-synuclein (alpha S), and transactive response DNA (TDP) binding protein 43 (TDP43)-immunoreactivity (-IR) increased with age. HP tau-IR was observed in 98% of the subjects; the locus coeruleus was solely affected in 46%, and 79% of the subjects were in Braak stages a to II. beta-Amyloid was seen in 47% of subjects and the Thal phase correlated with the HP tau Braak stage and age. Intermediate Alzheimer disease-related pathology (ADRP) was seen in 12%; 52% of the subjects with HP tau-IR fulfilled criteria for definite primary age-related tauopathy (PART). The incidence of concomitant pathology (alpha S, TDP43) did not differ between those with PART and those with ADRP but the former were younger. TDP43-IR was observed in 36%; the most frequently affected region was the medulla; alpha S-IR was observed in 19% of subjects. In 41% of the subjects from 80 to 89 years at death, 3 altered proteins were seen in the brain. Thus, altered proteins are common in the brains of cognitively unimpaired aged subjects; this should be considered while developing diagnostic biomarkers, particularly for identifying subjects at early stages of neurodegenerative diseases.

Place, publisher, year, edition, pages
Oxford University Press, 2016. Vol. 75, no 4, 316-325 p.
Keyword [en]
alpha-Synuclein; beta-Amyloid; Aging; Cognition; Hyperphosphorylated-tau; Immunohistochemistry; Transactive response DNA binding protein 43
National Category
Neurology
Identifiers
URN: urn:nbn:se:uu:diva-277213DOI: 10.1093/jnen/nlw002ISI: 000375797000004PubMedID: 26979082OAI: oai:DiVA.org:uu-277213DiVA: diva2:904071
Available from: 2016-02-18 Created: 2016-02-18 Last updated: 2017-11-30Bibliographically approved
In thesis
1. Altered proteins in the aging brain
Open this publication in new window or tab >>Altered proteins in the aging brain
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The classification of neurodegenerative disorders is based on the major component of the protein aggregates in the brain. The most common altered proteins associated with neurodegeneration are Hyperphosphorylated tau (HPt), beta amyloid (Aβ), alpha-synclein (αS) and transactive response DNA binding protein 43 (TDP43). In this study we assessed the incidence and the neuroanatomical distribution of proteins associated with neurodegeneration in the brain tissue of cognitively unimpaired subjects.

We demonstrated the early involvement of the Locus Coeruleus (LC) with HPt pathology in cognitively unimpaired mid aged subjects, a finding which supports the notion that LC is an initiation site of HPt pathology. This may suggest that development of clinical assessment techniques and radiological investigations reflecting early LC alterations may help in identifying subjects with early stages of neurodegeneration.

Furthermore, we studied a large cohort of cognitively unimpaired subjects with age at death ≥50 years and we applied the National Institute on Aging –Alzheimer’s disease (AD) Association (NIA-AA) guidelines for the assessment of AD related neuropathological changes. Interestingly, a considerable percentage of the subjects were classified as having an intermediate level of AD pathology. We also showed that the altered proteins;  HPt , Aβ, αS, and TDP43 are frequently seen in the brain of cognitively unimpaired subjects with age at death ≥50 years, the incidence of these proteins increased significantly with age. This finding suggests that neurodegeneration has to be extensive to cause functional disturbance and clinical symptoms.

Moreover, we investigated the correlation between AD related pathology in cortical biopsies, the AD / cerebrospinal fluid (CSF) biomarkers and the Mini Mental State examination (MMSE) scores in a cohort of idiopathic Normal Pressure Hydrocephalus (iNPH) patients. We demonstrated that AD/ CSF biomarkers and MMSE scores reflect AD pathology in the cortical biopsies obtained from iNPH patients. 

In conclusion, this study shows that the altered proteins associated with neurodegeneration are frequently seen in the brain tissue of cognitively unimpaired aged subjects. This fact should be considered while developing diagnostic biomarkers for identification of subjects at early stages of the disease, in order to introduce therapeutic intervention prior to the occurrence of significant cognitive impairment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1182
Keyword
Cognitively unimpaired subjects, Hyperphosphorylated tau, Beta amyloid, Alpha-synclein, Transactive response DNA binding protein 43
National Category
Medical and Health Sciences
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-277214 (URN)978-91-554-9482-7 (ISBN)
Public defence
2016-04-08, Fåhraeussalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-03-18 Created: 2016-02-18 Last updated: 2016-04-04

Open Access in DiVA

fulltext(178 kB)145 downloads
File information
File name FULLTEXT01.pdfFile size 178 kBChecksum SHA-512
f24b301e309eb22b06ed2acef5a23159aa93229019783250ec80b5aa96fa1124ed3e8178e40482fd2c22db743a66982f6ea7cd63f8591cbceb58488c6f137e2b
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Libard, SylwiaPopova, SvetlanaAlafuzoff, Irina

Search in DiVA

By author/editor
Libard, SylwiaPopova, SvetlanaAlafuzoff, Irina
By organisation
Department of Immunology, Genetics and Pathology
In the same journal
Journal of Neuropathology and Experimental Neurology
Neurology

Search outside of DiVA

GoogleGoogle Scholar
Total: 145 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 508 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf