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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 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.
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.
| Original language | English |
|---|---|
| Qualification | Doctor |
| Awarding Institution |
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| Supervisors/Advisors |
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| Award date | 2007 Dec 14 |
| Publisher | |
| ISBN (Print) | 978-91-85897-53-7 |
| Publication status | Published - 2007 |
Bibliographical note
Defence detailsDate: 2007-12-14
Time: 14:00
Place: CRC main lecture hall (aula), Malmö University Hospital entrance 72, Malmö
External reviewer(s)
Name: Finsen, Bente
Title: Professor
Affiliation: Institut for Medicinsk Biologi, Syddansk Universitet, Odense, Denmark
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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.
Subject classification (UKÄ)
- Clinical Medicine
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Dive into the research topics of 'Alzheimer's disease and dementia with Lewy bodies: Special focus on the role of serpins'. Together they form a unique fingerprint.Research output
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Effects of Alzheimer's peptide and alpha1-antichymotrypsin on astrocyte gene expression
Baker, C., Nielsen, H., Minthon, L., Wright, H., Chappell, S., Okyere, J., May, S., Morgan, K., Kalsheker, N. & Janciauskiene, S., 2007, In: Neurobiology of Aging.Research output: Contribution to journal › Article › peer-review
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Plasma and CSF serpins in Alzheimer disease and dementia with Lewy bodies
Nielsen, H., Minthon, L., Londos, E., Blennow, K., Miranda, E., Perez, J., Crowther, D., Lomas, D. & Janciauskiene, S., 2007, In: Neurology. 69, 16, p. 1569-1579Research output: Contribution to journal › Article › peer-review
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Soluble adhesion molecules and angiotensin-converting enzyme in dementia.
Nielsen, H., Londos, E., Minthon, L. & Janciauskiene, S., 2007, In: Neurobiology of Disease. 26, p. 27-35Research output: Contribution to journal › Article › peer-review