A study of b-secretase cleaved Alzheimer amyloid precursor protein
Author: Sennvik, Kristina
Date: 2002-04-26
Location: Birkeaulan, Huddinge Universitetssjukhus
Time: 9.30
Department: Institutionen för klinisk neurovetenskap, arbetsterapi och äldrevårdsforskning (NEUROTEC) / Department of Clinical Neuroscience, Occupational Therapy and Elderly Care Research (NEUROTEC)
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Thesis (833.2Kb)
Abstract
Alzheimer's disease (AD) is characterized by the degeneration and loss of neurons, intracellular neurofibrillary tangles and the accumulation of extracellular senile plaques consisting mainly of beta-amyloid (A-beta). A-beta is generated from the amyloid precursor protein (APP) through sequential cleavage by proteases P- and gamma-secretase. Alternatively, APP may be cleaved within the A-beta region by alpha-secretase, preventing intact A-beta formation. Both the alpha- and beta-secretase cleavages result in the release of large soluble APP fragments called alpha- or beta-sAPP, respectively. The work presented in this thesis describes the processing and secretion of differentially cleaved APP.
The purpose of the study were to investigate the beta-secretase cleavage of APP. Paper I examined differentially cleaved APP as diagnostic markers for AD. It was concluded that soluble beta- secretase cleaved APP (beta-sAPP) levels in CSF do not change in AD, although soluble (alpha-secretase cleaved APP (alpha-sAPP) and total sAPP decreases. Paper II and III provided insights into the mechanisms of the alternative APP cleavages during apoptosis in two different cell systems. In a primary rat cortical culture system, calcium homeostasis and caspase actions proved to be important effectors of the beta-secretase cleavage. Expression of the Arctic APP mutation in human neuroblastoma cells increased the vulnerability to cell death and modified beta-sAPP secretion, stressing the role of FAD mutations in apoptosis and APP processing. The localization and content of beta-sAPP in brain was explored in paper IV. Altered beta-sAPP staining pattems indicated abnormal processing and transport of APP in AD brain.
In summary, (i) beta-sAPP in CSF, (ii) beta-sAPP secretion from apoptotic neurons and (iii) beta-sAPP in brain were analysed. The results indicated that altered processing and transport of APP takes place in AD and during apoptosis. Since APP processing is considered a key event in the pathological cascade leading to AD, the proteases that cleave APP and the regulation mechanisms of those proteases are prime therapeutic targets.
The purpose of the study were to investigate the beta-secretase cleavage of APP. Paper I examined differentially cleaved APP as diagnostic markers for AD. It was concluded that soluble beta- secretase cleaved APP (beta-sAPP) levels in CSF do not change in AD, although soluble (alpha-secretase cleaved APP (alpha-sAPP) and total sAPP decreases. Paper II and III provided insights into the mechanisms of the alternative APP cleavages during apoptosis in two different cell systems. In a primary rat cortical culture system, calcium homeostasis and caspase actions proved to be important effectors of the beta-secretase cleavage. Expression of the Arctic APP mutation in human neuroblastoma cells increased the vulnerability to cell death and modified beta-sAPP secretion, stressing the role of FAD mutations in apoptosis and APP processing. The localization and content of beta-sAPP in brain was explored in paper IV. Altered beta-sAPP staining pattems indicated abnormal processing and transport of APP in AD brain.
In summary, (i) beta-sAPP in CSF, (ii) beta-sAPP secretion from apoptotic neurons and (iii) beta-sAPP in brain were analysed. The results indicated that altered processing and transport of APP takes place in AD and during apoptosis. Since APP processing is considered a key event in the pathological cascade leading to AD, the proteases that cleave APP and the regulation mechanisms of those proteases are prime therapeutic targets.
List of papers:
I. Sennvik K, Fastbom J, Blomberg M, Wahlund LO, Winblad B, Benedikz E (2000). Levels of alpha- and beta-secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimers disease patients. Neurosci Lett. 278(3): 169-72.
Pubmed
II. Sennvik K, Benedikz E, Fastbom J, Sundstrom E, Winblad B, Ankarcrona M (2001). Calcium ionophore A23187 specifically decreases the secretion of beta-secretase cleaved amyloid precursor protein during apoptosis in primary rat cortical cultures. J Neurosci Res. 63(5): 429-37.
Pubmed
III. Sennvik K, Nilsberth C, Stenh C, Lannfelt L, Benedikz E (2002). The Arctic Alzheimer mutation enhances sensitivity to toxic stress in human neuroblastoma cells. Neurosci Lett. [Accepted]
IV. Sennvik K, Bogdanovic N, Volkmann I, Fastbom J, Benedikz E (2002). Beta-secretase cleaved amyloid precursor protein in Alzheimer brain: a morphologic study. [Manuscript]
I. Sennvik K, Fastbom J, Blomberg M, Wahlund LO, Winblad B, Benedikz E (2000). Levels of alpha- and beta-secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimers disease patients. Neurosci Lett. 278(3): 169-72.
Pubmed
II. Sennvik K, Benedikz E, Fastbom J, Sundstrom E, Winblad B, Ankarcrona M (2001). Calcium ionophore A23187 specifically decreases the secretion of beta-secretase cleaved amyloid precursor protein during apoptosis in primary rat cortical cultures. J Neurosci Res. 63(5): 429-37.
Pubmed
III. Sennvik K, Nilsberth C, Stenh C, Lannfelt L, Benedikz E (2002). The Arctic Alzheimer mutation enhances sensitivity to toxic stress in human neuroblastoma cells. Neurosci Lett. [Accepted]
IV. Sennvik K, Bogdanovic N, Volkmann I, Fastbom J, Benedikz E (2002). Beta-secretase cleaved amyloid precursor protein in Alzheimer brain: a morphologic study. [Manuscript]
Issue date: 2002-04-05
Rights:
Publication year: 2002
ISBN: 91-7349-184-5
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