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

Research output: ThesisDoctoral Thesis (compilation)

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.

Details

Authors
  • Henrietta Nielsen
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Clinical Medicine
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
Award date2007 Dec 14
Publisher
  • Chronic Inflammatory and Degenerative Diseases Research Unit
Print ISBNs978-91-85897-53-7
Publication statusPublished - 2007
Publication categoryResearch

Bibliographic note

Defence details Date: 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 --- 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.

Total downloads

No data available

Related research output

Crystal Baker, Henrietta Nielsen, Lennart Minthon, HT Wright, Sally Chappell, John Okyere, Sean May, Kevin Morgan, Noor Kalsheker & Sabina Janciauskiene, 2007, In: Neurobiology of Aging.

Research output: Contribution to journalArticle

Henrietta Nielsen, Lennart Minthon, Elisabet Londos, Kaj Blennow, Elena Miranda, Juan Perez, Damian Crowther, David Lomas & Sabina Janciauskiene, 2007, In: Neurology. 69, 16, p. 1569-1579

Research output: Contribution to journalArticle

Henrietta Nielsen, Elisabet Londos, Lennart Minthon & Sabina Janciauskiene, 2007, In: Neurobiology of Disease. 26, p. 27-35

Research output: Contribution to journalArticle

View all (3)