A study of b-secretase cleaved Alzheimer amyloid precursor protein

<p>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.</p><p>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.</p><p>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.</p><h3>List of scientific papers</h3><p>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. <br><a href="https://pubmed.ncbi.nlm.nih.gov/10653020">https://pubmed.ncbi.nlm.nih.gov/10653020</a><br><br></p><p>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. <br><a href="https://pubmed.ncbi.nlm.nih.gov/11223918">https://pubmed.ncbi.nlm.nih.gov/11223918</a><br><br></p><p>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]</p><p>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]</p>