Alzheimer Disease: Ye Y

Lu Y, Lv Y, Ye Y, Wang Y, Hong Y, Fortini ME, Zhong Y, Xie Z. · State Key Laboratory of Biomembrane and Membrane Biotechnology, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing, China 100084. · FASEB J. · Pubmed #17428965 links to  free full text

Abstract: It has been shown that presenilin is involved in maintaining Ca2+ homeostasis in neurons, including regulating endoplasmic reticulum (ER) Ca2+ storage. From studies of primary cultures and cell lines, however, its role in stress-induced responses is still controversial. In the present study we analyzed the effects of presenilin mutations on membrane currents and synaptic functions in response to stress using an in vivo preparation. We examined voltage-gated K+ and Ca2+ currents at the Drosophila larval neuromuscular junction (NMJ) with voltage-clamp recordings. Our data showed that both currents were generally unaffected by loss-of-function or Alzheimer's disease (AD) -associated presenilin mutations under normal or stress conditions induced by heat shock (HS) or ER stress. In larvae expressing the mutant presenilins, prolonged Ca2+ tail current, reflecting slower deactivation kinetics of Ca2+ channels, was observed 1 day after stress treatments were terminated. It was further demonstrated that the L-type Ca2+ channel was specifically affected under these conditions. Moreover, synaptic plasticity at the NMJ was reduced in larvae expressing the mutant presenilins. At the behavioral level, memory in adult flies was impaired in the presenilin mutants 1 day after HS. The results show that presenilin function is important during the poststress period and its impairment contributes to memory dysfunction observed during adaptation to normal conditions after stress. Our findings suggest a new stress-related mechanism by which presenilin may be implicated in the neuropathology of AD.

Seidner GA, Ye Y, Faraday MM, Alvord WG, Fortini ME. · Laboratory of Protein Dynamics and Signaling, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702, USA. · Curr Biol. · Pubmed #16713961 No free full text.

Abstract: To assess the potential of Drosophila to analyze clinically graded aspects of human disease, we developed a transgenic fly model to characterize Presenilin (PS) gene mutations that cause early-onset familial Alzheimer's disease (FAD). FAD exhibits a wide range in severity defined by ages of onset from 24 to 65 years . PS FAD mutants have been analyzed in mammalian cell culture, but conflicting data emerged concerning correlations between age of onset and PS biochemical activity . Choosing from over 130 FAD mutations in Presenilin-1, we introduced 14 corresponding mutations at conserved residues in Drosophila Presenilin (Psn) and assessed their biological activity in transgenic flies by using genetic, molecular, and statistical methods. Psn FAD mutant activities were tightly linked to their age-of-onset values, providing evidence that disease severity in humans primarily reflects differences in PS mutant lesions rather than contributions from unlinked genetic or environmental modifiers. Our study establishes a precedent for using transgenic Drosophila to study clinical heterogeneity in human disease.

Ye Y, Fortini ME. · Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · J Cell Biol. · Pubmed #10491396 links to  free full text

Abstract: Mutant human presenilins cause early-onset familial Alzheimer's disease and render cells susceptible to apoptosis in cultured cell models. We show that loss of presenilin function in Drosophila melanogaster increases levels of apoptosis in developing tissues. Moreover, overexpression of presenilin causes apoptotic and neurogenic phenotypes resembling those of Presenilin loss-of-function mutants, suggesting that presenilin exerts a dominant negative effect when expressed at high levels. In Drosophila S2 cells, Psn overexpression leads to reduced Notch receptor synthesis affecting levels of the intact approximately 300-kD precursor and its approximately 120-kD processed COOH-terminal derivatives. Presenilin-induced apoptosis is cell autonomous and can be blocked by constitutive Notch activation, suggesting that the increased cell death is due to a developmental mechanism that eliminates improperly specified cell types. We describe a genetic model in which the apoptotic activities of wild-type and mutant presenilins can be assessed, and we find that Alzheimer's disease-linked mutant presenilins are less effective at inducing apoptosis than wild-type presenilin.

Ye Y, Lukinova N, Fortini ME. · Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia 19104, USA. · Nature. · Pubmed #10206647 No free full text.

Abstract: Presenilin proteins have been implicated both in developmental signalling by the cell-surface protein Notch and in the pathogenesis of Alzheimer's disease. Loss of presenilin function leads to Notch/lin-12-like mutant phenotypes in Caenorhabditis elegans and to reduced Notch1 expression in the mouse paraxial mesoderm. In humans, presenilins that are associated with Alzheimer's disease stimulate overproduction of the neurotoxic 42-amino-acid beta-amyloid derivative (Abeta42) of the amyloid-precursor protein APP. Here we describe loss-of-function mutations in the Drosophila Presenilin gene that cause lethal Notch-like phenotypes such as maternal neurogenic effects during embryogenesis, loss of lateral inhibition within proneural cell clusters, and absence of wing margin formation. We show that presenilin is required for the normal proteolytic production of carboxy-terminal Notch fragments that are needed for receptor maturation and signalling, and that genetically it acts upstream of both the membrane-bound form and the activated nuclear form of Notch. Our findings provide evidence for the existence of distinct processing sites or modifications in the extracellular domain of Notch. They also link the role of presenilin in Notch signalling to its effect on amyloid production in Alzheimer's disease.