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Alzheimer's disease and dementia with Lewy bodies: Special focus on the role of serpins

Nielsen, Henrietta LU (2007) In Lund University Faculty of Medicine Doctoral Dissertation Series 2007:175.
Abstract
Serine protease inhibitors (Serpins) are involved in the pathogenesis of neurodegenerative dementia, including

the two most common types, Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). The pathological characteristics of AD include senile plaques, mainly composed of aggregated amyloid-beta peptide (Abeta1-42), but also serpins, and neurofibrillary tangles of hyperphosphorylated tau protein. Pathological hallmarks of DLB include aggregates of alpha-synuclein (Lewy bodies), however, co-existing AD pathology is also frequently found. In the present work, we have investigated the role of three serpins, namely alpha1-antichymyotrypsin, alpha1-antitrypsin and neuroserpin, in the context of AD and DLB.

We have... (More)
Serine protease inhibitors (Serpins) are involved in the pathogenesis of neurodegenerative dementia, including

the two most common types, Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). The pathological characteristics of AD include senile plaques, mainly composed of aggregated amyloid-beta peptide (Abeta1-42), but also serpins, and neurofibrillary tangles of hyperphosphorylated tau protein. Pathological hallmarks of DLB include aggregates of alpha-synuclein (Lewy bodies), however, co-existing AD pathology is also frequently found. In the present work, we have investigated the role of three serpins, namely alpha1-antichymyotrypsin, alpha1-antitrypsin and neuroserpin, in the context of AD and DLB.

We have shown that alpha1-antichymotrypsin: (i) renders the oligomer formation profile of incubated Abeta1-42, favouring dimer formation; (ii) under certain conditions appears to protect Abeta1-42 from chymotrypsin digestion and;(iii) in combination with soluble forms of Abeta1-42, significantly affects the global gene expression of

primary fetal human astrocytes; (iv) can influence binding and, potentially, uptake of aggregated Abeta1-42 in

primary adult human astrocytes.



In two clinical studies we have: (i) for the first time, determined cerebrospinal fluid levels of neuroserpin and

established a link to AD as significantly higher levels of neuroserpin were found in AD patients than in

non-demented controls and DLB patients; (ii) showed that higher levels of cerebrospinal fluid alpha1-antitrypsin and plasma alpha1-antichymotrypsin correlate to lower cognitive function in patients with DLB and AD, respectively; (iii) showed that patients with AD and DLB have higher levels of intercellular adhesion molecule-1 and platelet endothelial cell adhesion molecule-1.



Our findings support the statement that inflammatory and vascular mechanisms are involved in dementia

pathogenesis and suggest that serpins most likely are involved in the processes leading to cognitive

dysfunction. Further research is needed to assess the distinct actions of serpins in the mechanisms leading to

neurodegeneration and dementia. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Finsen, Bente, Institut for Medicinsk Biologi, Syddansk Universitet, Odense, Denmark
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2007:175
publisher
Chronic Inflammatory and Degenerative Diseases Research Unit
defense location
CRC main lecture hall (aula), Malmö University Hospital entrance 72, Malmö
defense date
2007-12-14 14:00:00
ISSN
1652-8220
ISBN
978-91-85897-53-7
language
English
LU publication?
yes
additional info
The dissertation is based on the following papers: Paper I: A Complex of Alzheimer’s Aβ1-42 Peptide with α1-Antichymotrypsin: In vitro Study of its Formation and Breakdown. Asplund A, Nielsen HM, Sun Y-X, Janciauskiene S, Desai UR, Wright HT. Submitted. Paper II: Effects of Alzheimer's peptide and alpha1-antichymotrypsin on astrocyte gene expression. Baker C, Nielsen HM, Minthon L, Wright HT, Chappell S, Okyere J, May S, Morgan K, Kalsheker N, Janciauskiene SM. Neurobiology of Aging. 2007 Jan;28(1):51-61. Epub 2005 Dec 20. Paper III: Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies. Nielsen HM, Minthon L, Londos E, Blennow K, Miranda E, Perez J, Crowther DC, Lomas DA, Janciauskiene SM. Neurology. 2007 Oct 16;69(16):1569-79. Epub 2007 Aug 29. Paper IV: Soluble adhesion molecules and angiotensin-converting enzyme in dementia. Nielsen HM, Londos E, Minthon L, Janciauskiene SM. Neurobiology of Disease. 2007 Apr;26(1):27-35. Epub 2007 Jan 31. Paper V: Binding and uptake of aggregated Aβ1-42 by primary human astrocytes in vitro. Nielsen HM, Veerhuis R, Holmqvist B, Janciauskiene SM. Manuscript.
id
054a9e62-a169-4e1f-8352-08e729544394 (old id 621728)
date added to LUP
2016-04-01 15:29:58
date last changed
2023-04-18 19:56:23
@phdthesis{054a9e62-a169-4e1f-8352-08e729544394,
  abstract     = {{Serine protease inhibitors (Serpins) are involved in the pathogenesis of neurodegenerative dementia, including<br/><br>
the two most common types, Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). The pathological characteristics of AD include senile plaques, mainly composed of aggregated amyloid-beta peptide (Abeta1-42), but also serpins, and neurofibrillary tangles of hyperphosphorylated tau protein. Pathological hallmarks of DLB include aggregates of alpha-synuclein (Lewy bodies), however, co-existing AD pathology is also frequently found. In the present work, we have investigated the role of three serpins, namely alpha1-antichymyotrypsin, alpha1-antitrypsin and neuroserpin, in the context of AD and DLB. <br/><br>
We have shown that alpha1-antichymotrypsin: (i) renders the oligomer formation profile of incubated Abeta1-42, favouring dimer formation; (ii) under certain conditions appears to protect Abeta1-42 from chymotrypsin digestion and;(iii) in combination with soluble forms of Abeta1-42, significantly affects the global gene expression of<br/><br>
primary fetal human astrocytes; (iv) can influence binding and, potentially, uptake of aggregated Abeta1-42 in<br/><br>
primary adult human astrocytes.<br/><br>
<br/><br>
In two clinical studies we have: (i) for the first time, determined cerebrospinal fluid levels of neuroserpin and<br/><br>
established a link to AD as significantly higher levels of neuroserpin were found in AD patients than in<br/><br>
non-demented controls and DLB patients; (ii) showed that higher levels of cerebrospinal fluid alpha1-antitrypsin and plasma alpha1-antichymotrypsin correlate to lower cognitive function in patients with DLB and AD, respectively; (iii) showed that patients with AD and DLB have higher levels of intercellular adhesion molecule-1 and platelet endothelial cell adhesion molecule-1.<br/><br>
<br/><br>
Our findings support the statement that inflammatory and vascular mechanisms are involved in dementia<br/><br>
pathogenesis and suggest that serpins most likely are involved in the processes leading to cognitive<br/><br>
dysfunction. Further research is needed to assess the distinct actions of serpins in the mechanisms leading to<br/><br>
neurodegeneration and dementia.}},
  author       = {{Nielsen, Henrietta}},
  isbn         = {{978-91-85897-53-7}},
  issn         = {{1652-8220}},
  language     = {{eng}},
  publisher    = {{Chronic Inflammatory and Degenerative Diseases Research Unit}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Alzheimer's disease and dementia with Lewy bodies: Special focus on the role of serpins}},
  url          = {{https://lup.lub.lu.se/search/files/4406260/621763.pdf}},
  volume       = {{2007:175}},
  year         = {{2007}},
}