Spelling suggestions: "subject:"presenilin""
1 |
The role of mutant presenilin-1 in apoptosis and the pathogenesis of familial Alzheimer's disease /Weihl, Conrad Christian. January 1999 (has links)
Thesis (Ph. D.)--University of Chicago, Committee on Neurobiology, August 1999. / Includes bibliographical references. Also available on the Internet.
|
2 |
The generation, and the neurochemical and behavioural characterization of transgenic mice carrying the human presenilin-1 gene with or without the Leu235Pro mutation associated with Afzheimer's disease /Huang, Xiangao. January 2001 (has links)
Thesis (Ph. D.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 159-193).
|
3 |
The generation, and the neurochemical and behavioural characterizationof transgenic mice carrying the human presenilin-1 gene with orwithout the Leu235Pro mutation associated with Afzheimer's disease黃憲高, Huang, Xiangao. January 2001 (has links)
published_or_final_version / Physiology / Doctoral / Doctor of Philosophy
|
4 |
Some studies on the cholinergic and somatostatinergic systems in the brain of mouse alzheimer models with transgenes for amyloid precursorprotein (APP) and presenilin許瑰蓮, Xu, Guilian. January 2000 (has links)
published_or_final_version / Physiology / Doctoral / Doctor of Philosophy
|
5 |
Some studies on the cholinergic and somatostatinergic systems in the brain of mouse alzheimer models with transgenes for amyloid precursor protein (APP) and presenilinXu, Guilian. January 2000 (has links)
Thesis (Ph. D.)--University of Hong Kong, 2001. / Includes bibliographical references (leaves 150-191).
|
6 |
Effect of novel Chinese specific presenilin-1 V97L mutation on intracellular calcium homeostasis in human neuroblastomaHung, Chun-hin, 孔進軒 January 2013 (has links)
Presenilin-1 (PS1) mutations caused by the PSEN1 gene mutations are the major cause of early onset familial Alzheimer’s disease (EOFAD). Two Chinesespecific EOFAD related PS1 mutations, V97L and A136G, have been found. Studies suggested that V97L mutation lead to the overexpression of Aβ42 and tau hyperphosphorylation, which are the major hallmarks of Alzheimer’s disease (AD), while properties of A136G were unclear. Since calcium dysregulation was suggested to play an important role in AD, the research project investigated if V97L and A136G mutations also lead to altered endoplasmic reticulum (ER) 〖Ca〗^(2+) regulation. SH-SY5Y cells transduced with retrovirus carrying V97L mutant or A136 mutant PSEN1 were used as the experiment models.
In Western blotting, while the PS1 expression level was unaffected in V97L mutant, the expression level was significantly lower in A136G mutant. In carbachol (CCh) perfusion experiment, V97L mutant was found to exaggerate ER 〖Ca〗^(2+) release when stimulated by higher concentration (30, 100 and 300 μM) CCh, while A136G mutant exaggerated ER Ca2+ release when stimulated by 30 μM and 300 μM CCh, but not 100 μM CCh. In 5% fetal bovine serum (FBS) perfusion experiment, both V97L and A136G mutants were found to sensitize 〖Ca〗^(2+) oscillation, which the sensitization effect of V97L was 3 folds of A136G.
The results suggested that V97L mutation exaggerates ER 〖Ca〗^(2+) release, possibly via interaction with IP3R. However the results of A136G were inconclusive and contradicting, therefore further investigation is needed. / published_or_final_version / Physiology / Master / Master of Medical Sciences
|
7 |
Chromosome missegregation in Alzheimer's disease caused by presenilin 1 /Boeras, Debrah I. January 2005 (has links)
Dissertation (Ph.D.)--University of South Florida, 2005. / Includes vita. Includes bibliographical references (leaves 164-190). Also available online.
|
8 |
Apolipoprotein E and Mitochondria-associated Endoplasmic Reticulum Membrane DysfunctionTambini, Marc D. January 2015 (has links)
Despite the tremendous advances of the last century, the cause of Alzheimer disease (AD) remains unclear. Genetic analysis of families with Alzheimer disease has revealed a disease-associated variant of the APOE gene, which encodes apolipoprotein E, a transporter of lipids in the blood and central nervous system. The effect of the AD-associated isotype, termed ApoE-E4, on disease risk has been validated, though it is unclear by what mechanism apoE-E4 confers AD risk. Mitochondria have long been implicated in AD pathogenesis, as the canonical histopathological findings of amyloid plaques and tau tangles occur in the setting of mitochondrial dysfunction. The disrupted processes include calcium homeostasis, cholesterol metabolism, phospholipid synthesis, and mitochondrial dynamics, and are all regulated by a subcompartment of the ER that is in physical contact with mitochondria. This compartment, called the mitochondria-associated ER membrane, or MAM, has been found to be overactive in AD patient cell lines and cell models of AD. Given that MAM is dysfunctional in AD and that ApoE-ε4 is the most important risk factor for AD, this dissertation examines if ApoE4 contributes to the MAM dysfunction seen in AD. The MAM dysfunction seen in AD patients and in cell models of AD has been best characterized in the context of familial AD, and it is the purpose of this study to extend those findings to the more common, sporadic, form of the disease. Familial AD is the result of autosomal dominant mutations in one of three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), or presenilin 2 (PSEN2). APP is the protein from which amyloid-beta, the component of amyloid plaques, is cleaved. The presenilins constitute the enzymatic core of the γ-secretase complex, which cleaves amyloid-beta from a precursor APP molecule. Both PSEN1 (PS1) and PSEN2 (PS2) localize at the MAM, and their action is speculated to influence MAM activity. Fibroblasts from familial AD patients, which contained mutations in APP, PSEN1 or PSEN2, showed a marked increase in MAM activity when compared to that of age-matched controls. In mouse embryonic fibroblasts, one can recapitulate this increased MAM activity by knocking out presenilins 1 and 2. In these Psen1/2 double knockout (DKO) cells, the typical measures of MAM function, i.e. increased cholesteryl ester and phosphatidylethanolamine synthesis, calcium transport from ER to mitochondria, and co-localization of ER and mitochondria by confocal and electron microscopy, mimicked the same phenotype found in fibroblasts obtained from familial AD patients, which suggests that the presenilins are negative regulators of ER-mitochondrial apposition. The precise mechanism by which they regulate the ER-mitochondria interface, whether directly as part of a tethering complex, or indirectly though the metabolism of APP-derived substrates, is unclear. While the effect of familial AD mutations on MAM has been characterized, the mechanism of mitochondrial dysfunction seen in the more common sporadic form of the disease remains obscure. Sporadic AD patients harbor no mutations in APP, PSEN1, or PSEN2, but rather inherit mutations in other genes which do not guarantee the development of the disease, but are instead considered risk factors. The most important of these risk factors, in terms of both amount of AD risk conferred and prevalence in the population, is ApoE. Embedded in the phospholipid monolayer of lipoproteins, ApoE is involved in the transport of phospholipids, cholesterol, and cholesteryl esters in plasma and the central nervous system (CNS). In the CNS, it is the most abundant apolipoprotein, and is secreted primarily by astrocytes and taken up by neurons. Once endocytosed, ApoE can follow three different pathways: degradation by the lysosome, intracellular retention in early endosomes, or re-lipidation and re-secretion out of the cell. Our approach takes advantage of the physiological role of ApoE as part of a high densitylike lipoprotein particle (HDL). Using astrocytes from ApoE targeted gene replacement mice in which murine APOE has been replaced by either human APOE-E3 or human APOE-E4, cultured media containing ApoE3 and ApoE4-lipoproteins can be produced and applied to target cells that do not express ApoE, such as neurons or fibroblasts. These target cells can then be analyzed for MAM activity. To examine the contribution of ApoE towards MAM dysfunction, target cells, either neurons or fibroblasts, were grown in the presence of astrocyte conditioned media (ACM) from ApoE targeted gene replacement mice. Several measures of phospholipid and cholesteryl ester synthesis were performed to analyzed MAM function. To confirm that the alterations in phospholipid synthesis were the result of altered MAM activity, the same assay was performed in cells in which a protein tethers that bind mitochondria and ER were genetically ablated. Finally, to confirm that the effects seen were the result of the HDL particles and not the result of other components of the ACM, lipoproteins were extracted from ACM by density ultracentrifugation and applied to fibroblasts. In all of the assays performed, ApoE4 conditioned media or ApoE4 isolated lipoproteins were able to induce a significant increase in MAM activity, whereas ApoE4 from recombinant sources did not. These data suggest a contribution of ApoE4 towards MAM dysfunction seen in AD. The mechanism of these ApoE4 induced MAM alterations remains to be deduced. One may speculate that given the role of ApoE in cholesterol transport outside of the cell, its intracellular retention may impact the distribution of cholesterol within the cell. MAM is a cholesterol rich subdomain with lipid raft-like properties, and any change in the cholesterol content or lipid nature of this membrane may alter its activity. To test this hypothesis, MAM was biochemically extracted from ApoE3 and ApoE4 treated cells and analyzed for cholesterol and lipidomic content. The results described in this thesis demonstrate an AD-like effect in wildtype cells when treated with ApoE-E4, and that the mechanism for these alterations may be due to disturbances in cholesterol distribution in the MAM.
|
Page generated in 0.0588 seconds