A study of b-secretase cleaved Alzheimer amyloid precursor protein

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 1 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 11 and 111 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

Tau-4R suppresses proliferation and promotes neuronal differentiation in the hippocampus of tau knockin/knockout mice

Differential isoform expression and phosphorylation of protein tau are believed to regulate the assembly and stabilization of microtubuli in fetal and adult neurons. To define the functions of tau in the developing and adult brain, we generated transgenic mice expressing the human tau-4R/2N (htau-4R) isoform on a murine tau null background, by a knockout/knockin approach (tau-KOKI). The main findings in these mice were the significant increases in hippocampal volume and neuronal number, which were sustained throughout adult life and paralleled by improved cognitive functioning. The increase in hippocampal size was found to be due to increased neurogenesis and neuronal survival. Proliferation and neuronal differentiation were further analyzed in primary hippocampal cultures from tau-KOKI mice, before and after htau-4R expression onset. In absence of tau, proliferation increased and both neurite and axonal outgrowth were reduced. Htau-4R expression suppressed proliferation, promoted neuronal differentiation, and restored neurite and axonal outgrowth. We suggest that the tau-4R isoform essentially contributes to hippocampal development by controlling proliferation and differentiation of neuronal precursors.status: publishe