scholarly journals Expression of familial Alzheimer disease presenilin 1 gene attenuates vesicle traffic and reduces peptide secretion in cultured astrocytes devoid of pathologic tissue environment

Glia ◽  
2015 ◽  
Vol 64 (2) ◽  
pp. 317-329 ◽  
Author(s):  
Matjaž Stenovec ◽  
Saša Trkov ◽  
Eva Lasič ◽  
Slavica Terzieva ◽  
Marko Kreft ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Presenilin 1 ◽  
Vesicle Traffic ◽  
Cultured Astrocytes ◽  
Familial Alzheimer Disease ◽  
Peptide Secretion

scholarly journals Overexpression in Neurons of Human Presenilin-1 or a Presenilin-1 Familial Alzheimer Disease Mutant Does Not Enhance Apoptosis

1998 ◽  
Vol 18 (23) ◽  
pp. 9790-9799 ◽  
Author(s):  
Sherry Bursztajn ◽  
Richard DeSouza ◽  
Donna L. McPhie ◽  
S. A. Berman ◽  
Junichi Shioi ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Presenilin 1 ◽  
Familial Alzheimer Disease

scholarly journals Presenilin1 familial Alzheimer disease mutants inactivate EFNB1- and BDNF-dependent neuroprotection against excitotoxicity by affecting neuroprotective complexes of N-methyl-d-aspartate receptor

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Md Al Rahim ◽  
Yonejung Yoon ◽  
Christina Dimovasili ◽  
Zhiping Shao ◽  
Qian Huang ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
De Novo ◽  
Neuronal Damage ◽  
Trophic Factors ◽  
Presenilin 1 ◽  
Wild Type ◽  
Receptor Complexes ◽  
Aspartate Receptor ◽  
Familial Alzheimer Disease ◽  
The Stability

Abstract Excitotoxicity is thought to play key roles in brain neurodegeneration and stroke. Here we show that neuroprotection against excitotoxicity by trophic factors EFNB1 and brain-derived neurotrophic factor (called here factors) requires de novo formation of ‘survival complexes’ which are factor-stimulated complexes of N-methyl-d-aspartate receptor with factor receptor and presenilin 1. Absence of presenilin 1 reduces the formation of survival complexes and abolishes neuroprotection. EPH receptor B2- and N-methyl-d-aspartate receptor-derived peptides designed to disrupt formation of survival complexes also decrease the factor-stimulated neuroprotection. Strikingly, factor-dependent neuroprotection and levels of the de novo factor-stimulated survival complexes decrease dramatically in neurons expressing presenilin 1 familial Alzheimer disease mutants. Mouse neurons and brains expressing presenilin 1 familial Alzheimer disease mutants contain increased amounts of constitutive presenilin 1–N-methyl-d-aspartate receptor complexes unresponsive to factors. Interestingly, the stability of the familial Alzheimer disease presenilin 1–N-methyl-d-aspartate receptor complexes differs from that of wild type complexes and neurons of mutant-expressing brains are more vulnerable to cerebral ischaemia than neurons of wild type brains. Furthermore, N-methyl-d-aspartate receptor-mediated excitatory post-synaptic currents at CA1 synapses are altered by presenilin 1 familial Alzheimer disease mutants. Importantly, high levels of presenilin 1–N-methyl-d-aspartate receptor complexes are also found in post-mortem brains of Alzheimer disease patients expressing presenilin 1 familial Alzheimer disease mutants. Together, our data identify a novel presenilin 1-dependent neuroprotective mechanism against excitotoxicity and indicate a pathway by which presenilin 1 familial Alzheimer disease mutants decrease factor-depended neuroprotection against excitotoxicity and ischaemia in the absence of Alzheimer disease neuropathological hallmarks which may form downstream of neuronal damage. These findings have implications for the pathogenic effects of familial Alzheimer disease mutants and therapeutic strategies.

scholarly journals Familial Alzheimer Disease Presenilin-1 Mutations Alter the Active Site Conformation of γ-secretase

2012 ◽  
Vol 287 (21) ◽  
pp. 17288-17296 ◽  
Author(s):  
De-Ming Chau ◽  
Christina J. Crump ◽  
Jennifer C. Villa ◽  
David A. Scheinberg ◽  
Yue-Ming Li
Keyword(s):  
Alzheimer Disease ◽  
Active Site ◽  
Presenilin 1 ◽  
Familial Alzheimer Disease ◽  
Active Site Conformation

Increased presence of amino-terminally-truncated Aβ-peptides in presenilin 1 early-onset familial Alzheimer disease

2000 ◽  
Vol 21 ◽  
pp. 194
Author(s):  
Claudio Russo ◽  
Takaomi C. Saido ◽  
Christine Hulette ◽  
Kathleen Price ◽  
Bernardino Ghetti ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Early Onset ◽  
Presenilin 1 ◽  
Aβ Peptides ◽  
Familial Alzheimer Disease

scholarly journals Familial Alzheimer disease–linked mutations specifically disrupt Ca2+ leak function of presenilin 1

2007 ◽  
Vol 117 (5) ◽  
pp. 1230-1239 ◽  
Author(s):  
Omar Nelson ◽  
Huiping Tu ◽  
Tianhua Lei ◽  
Mostafa Bentahir ◽  
Bart de Strooper ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Presenilin 1 ◽  
Familial Alzheimer Disease

scholarly journals The Alzheimer Disease-Causing Presenilin-1 L435F Mutation Causes Increased Production of Soluble Aβ43 Species in Patient-Derived iPSC-Neurons, Closely Mimicking Matched Patient Brain Tissue

2020 ◽  
Vol 79 (6) ◽  
pp. 592-604 ◽  
Author(s):  
Derek H Oakley ◽  
Mirra Chung ◽  
Naomi Klickstein ◽  
Caitlin Commins ◽  
Bradley T Hyman ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Brain Tissue ◽  
Case Series ◽  
Induced Pluripotent Stem Cell ◽  
Presenilin 1 ◽  
Gamma Secretase ◽  
Severe Reduction ◽  
Autopsy Brain Tissue ◽  
Familial Alzheimer Disease ◽  
Induced Pluripotent

Abstract Familial Alzheimer disease-causing mutations in Presenilin 1 (PSEN1) are generally thought to shift the processing of APP toward longer, more amyloidogenic Aβ fragments. However, certain PSEN1 mutations cause severe reduction in gamma secretase function when expressed in the homozygous state, thus challenging the amyloid hypothesis. We sought to evaluate the effects of one such mutation, PSEN1 L435F, in more physiologic conditions and genetic contexts by using human induced pluripotent stem cell (iPSC)-derived neurons from an individual with familial AD (fAD) linked to the PSEN1 L435F mutation, and compared the biochemical phenotype of the iPS-derived neurons with brain tissue obtained at autopsy from the same patient. Our results demonstrate that in the endogenous heterozygous state, the PSEN1 L435F mutation causes a large increase in soluble Aβ43 but does not change the overall levels of soluble Aβ40 or Aβ42 when compared with control iPSC-neurons. Increased pathologically phosphorylated tau species were also observed in PSEN1-mutant iPSC-neurons. Concordant changes in Aβ species were present in autopsy brain tissue from the same patient. Finally, the feasibility of using Aβ43 immunohistochemistry of brain tissue to identify fAD cases was evaluated in a limited autopsy case series with the finding that strong Aβ43 staining occurred only in fAD cases.

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