Partial Loss of Presenilin Impairs Age-Dependent Neuronal Survival in the Cerebral Cortex

Watanabe, Hirotaka; Iqbal, Minah; Jian, Zheng; Wines-Samuelson, Mary; Shen, Jie

doi:10.1523/jneurosci.3261-14.2014

Cited by 42 publications

(48 citation statements)

References 40 publications

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“…Previous work has shown that PS2 expression is up-regulated in the absence of PS1 (Watanabe et al, 2014), which may compensate for behavioral and synaptic deficits caused by PS1 deficiency. We therefore examined the impact of the L435F mutation on behavioral and synaptic phenotypes in a Psen2−/− background.…”

Section: Resultsmentioning

confidence: 99%

“…Further analysis of Psen conditional knockout mice with varying Psen2 gene dosage showed that partial inactivation of PS also results in age-dependent neurodegeneration, though with lesser severity and a later age of onset (Watanabe et al, 2014). To examine the impact of the L435F mutation on neuronal survival, relative to the Psen1 wild-type allele, we generated Psen1 F/L435F ; Psen2 −/− ; Camk2a-Cre mice and littermate Psen1 F/+ ; Psen2 −/− ; Camk2a-Cre and Psen1 F/F ; Psen2 −/− mice.…”

Section: Resultsmentioning

confidence: 99%

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Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease

Xia

Watanabe

et al. 2015

Neuron

209

229

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Summary Presenilins play essential roles in memory formation, synaptic function, and neuronal survival. Mutations in the Presenilin-1 (PSEN1) gene are the major cause of familial Alzheimer’s disease (FAD). How PSEN1 mutations cause FAD is unclear, and pathogenic mechanisms based on gain or loss of function have been proposed. Here, we generated Psen1 knockin (KI) mice carrying the FAD mutation L435F or C410Y. Remarkably, KI mice homozygous for either mutation recapitulate the phenotypes of Psen1−/− mice. Neither mutation altered Psen1 mRNA expression, but both abolished γ-secretase activity. Heterozygosity for the KI mutation decreased production of Aβ40 and Aβ42, increased the Aβ42/Aβ40 ratio, and exacerbated Aβ deposition. Furthermore, the L435F mutation impairs hippocampal synaptic plasticity and memory and causes age-dependent neurodegeneration in the aging cerebral cortex. Collectively, our findings reveal that FAD mutations can cause complete loss of Presenilin-1 function in vivo, suggesting that clinical PSEN mutations produce FAD through a loss-of-function mechanism.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease

Xia

Watanabe

et al. 2015

Neuron

209

229

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“…Specifically, we crossed Psen1 L435F KI mice to the Psen2 −/− background to enable more direct and accurate analysis of the phenotypic effects of the L435F mutation on PS1 function (Xia et al, 2015). Indeed, we previously found that loss of PS1 expression leads to up-regulation of PS2 expression (Watanabe et al, 2014), which would mask the effects of PS1 loss-of-function mutations. Curiously, Veugelen et al don’t object to the converse approach of overexpressing PSEN1 and APP .…”

Section: Discussionmentioning

confidence: 99%

Loss of Aβ43 Production Caused by Presenilin-1 Mutations in the Knockin Mouse Brain

Xia

Kelleher

Shen

2016

Neuron

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SUMMARY We recently reported that homozygous Presenilin-1 (Psen1) knockin (KI) mice carrying the familial Alzheimer’s disease (FAD) mutation L435F or C410Y recapitulate the phenotypes of Psen1−/− mice. Production and steady-state levels of Aβ40 and Aβ42 are undetectable in KI/KI brains and reduced in KI/+ brains, though the Aβ42/Aβ40 ratio is slightly increased in KI/+ brains. Moreover, the FAD mutation impairs synaptic function, learning and memory, and age-dependent neuronal survival in the adult brain. Here we extend our analysis of the effects of the L435F and C410Y mutations to the generation of Aβ43. Similar to Aβ40 and Aβ42, production of Aβ43 is undetectable in KI/KI brains and reduced in KI/+ brains. These results support our previous conclusions that the L435F and C410Y mutations cause loss of Presenilin function and γ-secretase activity, including impaired Aβ production in the brain. This Matters Arising Response paper addresses the Veugelen et al. Matters Arising paper.

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“…Evidence also suggests the regulation of the transcription factor EGR-1 may be regulated by APP, which may play a role in AD development and memory formation [265]. Mutations in NRF1 targets PSEN1 and PSEN2 may also lead to the development of neurodegenerative disease [266,267,268]. In addition PSEN1 and PSEN2 transcription, expression, promoter activity, and mRNA levels are influenced by the PARKIN protein [269].…”

Section: Mechanisms Of Actions Of Estrogenic Endocrine Disruptors mentioning

confidence: 99%

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

Preciados

Yoo

Roy

2016

IJMS

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During the development of an individual from a single cell to prenatal stages to adolescence to adulthood and through the complete life span, humans are exposed to countless environmental and stochastic factors, including estrogenic endocrine disrupting chemicals. Brain cells and neural circuits are likely to be influenced by estrogenic endocrine disruptors (EEDs) because they strongly dependent on estrogens. In this review, we discuss both environmental, epidemiological, and experimental evidence on brain health with exposure to oral contraceptives, hormonal therapy, and EEDs such as bisphenol-A (BPA), polychlorinated biphenyls (PCBs), phthalates, and metalloestrogens, such as, arsenic, cadmium, and manganese. Also we discuss the brain health effects associated from exposure to EEDs including the promotion of neurodegeneration, protection against neurodegeneration, and involvement in various neurological deficits; changes in rearing behavior, locomotion, anxiety, learning difficulties, memory issues, and neuronal abnormalities. The effects of EEDs on the brain are varied during the entire life span and far-reaching with many different mechanisms. To understand endocrine disrupting chemicals mechanisms, we use bioinformatics, molecular, and epidemiologic approaches. Through those approaches, we learn how the effects of EEDs on the brain go beyond known mechanism to disrupt the circulatory and neural estrogen function and estrogen-mediated signaling. Effects on EEDs-modified estrogen and nuclear respiratory factor 1 (NRF1) signaling genes with exposure to natural estrogen, pharmacological estrogen-ethinyl estradiol, PCBs, phthalates, BPA, and metalloestrogens are presented here. Bioinformatics analysis of gene-EEDs interactions and brain disease associations identified hundreds of genes that were altered by exposure to estrogen, phthalate, PCBs, BPA or metalloestrogens. Many genes modified by EEDs are common targets of both 17 β-estradiol (E2) and NRF1. Some of these genes are involved with brain diseases, such as Alzheimer’s Disease (AD), Parkinson’s Disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis, Autism Spectrum Disorder, and Brain Neoplasms. For example, the search of enriched pathways showed that top ten E2 interacting genes in AD—APOE, APP, ATP5A1, CALM1, CASP3, GSK3B, IL1B, MAPT, PSEN2 and TNF—underlie the enrichment of the Kyoto Encyclopedia of Genes and Genomes (KEGG) AD pathway. With AD, the six E2-responsive genes are NRF1 target genes: APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1. These genes are also responsive to the following EEDs: ethinyl estradiol (APBB2, DPYSL2, EIF2S1, ENO1, MAPT, and PAXIP1), BPA (APBB2, EIF2S1, ENO1, MAPT, and PAXIP1), dibutyl phthalate (DPYSL2, EIF2S1, and ENO1), diethylhexyl phthalate (DPYSL2 and MAPT). To validate findings from Comparative Toxicogenomics Database (CTD) curated data, we used Bayesian network (BN) analysis on microarray data of AD patients. We observed that both gender and NRF1 were associated with AD. The female NRF1 gene network is completely ...

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Partial Loss of Presenilin Impairs Age-Dependent Neuronal Survival in the Cerebral Cortex

Cited by 42 publications

References 40 publications

Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease

Presenilin-1 Knockin Mice Reveal Loss-of-Function Mechanism for Familial Alzheimer’s Disease

Loss of Aβ43 Production Caused by Presenilin-1 Mutations in the Knockin Mouse Brain

Estrogenic Endocrine Disrupting Chemicals Influencing NRF1 Regulated Gene Networks in the Development of Complex Human Brain Diseases

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