Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency

Herreman, An; Hartmann, Dieter; Annaert, Wim; Säftig, Paul; Craessaerts, Katleen; Serneels, Lutgarde; Umans, Lieve; Schrijvers, Vincent; Checler, Frédéric; Vanderstichele, Hugo; Baekelandt, Veerle; Dressel, Ralf; Cupers, Philippe; Huylebroeck, Danny; Zwijsen, An; Leuven, Fred Van; Strooper, Bart De

doi:10.1073/pnas.96.21.11872

Cited by 482 publications

(433 citation statements)

References 43 publications

Supporting

Mentioning

397

Contrasting

Order By: Relevance

“…However, this possibility seems unlikely because the decrease in the number of neural stem cells was found as well in PS1 −/− brains without any hemorrhage (2 of 12 brains). The disruption of the PS2 gene alone has little effect on the normal development of mice, but it enhances the phenotype in PS1 −/− embryos (Donoviel et al 1999;Herreman et al 1999). Consistent with this, no neurosphere colonies were found in the cultures of ganglionic eminence cells from E14.5 PS1 −/− ;PS2 +/− embryos.…”

Section: E145 Neural Stem Cells Are Depleted In the Ps1 −/− Brain Asupporting

confidence: 63%

Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells

et al. 2002

View full text Add to dashboard Cite

Neural stem cells, which exhibit self-renewal and multipotentiality, are generated in early embryonic brains and maintained throughout the lifespan. The mechanisms of their generation and maintenance are largely unknown. Here, we show that neural stem cells are generated independent of RBP-J , a key molecule in Notch signaling, by using RBP-J −/− embryonic stem cells in an embryonic stem cell-derived neurosphere assay. However, Notch pathway molecules are essential for the maintenance of neural stem cells; they are depleted in the early embryonic brains of RBP-J −/− or Notch1 −/− mice. Neural stem cells also are depleted in embryonic brains deficient for the presenilin1 (PS1) gene, a key regulator in Notch signaling, and are reduced in PS1 +/− adult brains. Both neuronal and glial differentiation in vitro were enhanced by attenuation of Notch signaling and suppressed by expressing an active form of Notch1. These data are consistent with a role for Notch signaling in the maintenance of the neural stem cell, and inconsistent with a role in a neuronal/glial fate switch.[Key Words: Presenilin; RBP-J ; embryonic stem cell; self-renewal; multipotentiality; cell cycle time]Received August 31, 2001; revised version accepted February 11, 2002. Neural stem cells, which are considered the ultimate lineage precursors to all neuronal and glial cells in the mammalian nervous system, are present not only in the developing brain but also in the adult brain Gage 2000). Although neural stem cells have a fundamental role in generating cellular diversity in the developing mammalian nervous system and in maintaining normal brain functions in adult brains (Lois and Alvarez-Buylla 1994;Tropepe et al. 1999;Shors et al. 2001), little is known concerning molecular mechanisms regulating the generation and maintenance of neural stem cells. In vitro, single neural stem cells proliferate to form clonally derived floating sphere colonies (neurospheres), which contain cells that, upon dissociation into single cells, give rise to new sphere colonies (self-renewal) and cells that can differentiate into neurons or glia (multipotentiality). Fibroblast growth factor-2 (FGF2)-responsive neural stem cells first appear in vivo at embryonic day (E) 8.5 and a separate and additive population of epidermal growth factor (EGF)-responsive neural stem cells arises from the earlier born FGF2-responsive stem cells by asymmetric division between E11 and E13 (Burrows et al. 1997;Mayer-Proschel et al. 1997;Tropepe et al. 1999). Both FGF2-responsive and EGF-responsive neural stem cells expand their populations and extend their cell cycle times during later embryogenesis (Martens et al. 2000). In the adult forebrain, neural stem cells are present as a relatively quiescent subpopulation in the subependyma, a remnant of the embryonic germinal zone (Morshead et al. 1994). This population persists into senescence, and the number is maintained throughout life (Tropepe et al. 1997). Thus, the generation and the size of the neural stem-cell population are tightly regul...

show abstract

Section: E145 Neural Stem Cells Are Depleted In the Ps1 −/− Brain Asupporting

confidence: 63%

Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells

et al. 2002

View full text Add to dashboard Cite

show abstract

“…In these animals the levels of C-terminal fragments of APP were 30 times increased as compared to normal, and Aβ40 and Aβ42 peptides were significantly reduced. These in vitro and in vivo data confirmed the hypothesis that PSEN1 facilitates the γ-secretase cleavage of APP.PSEN2 knockout mice are viable and phenotypically normal, and the absence of PSEN2 did not affect the Aβ production in neuronal cultures [159,160].To model the formation of NFT pathology, and to investigate the relationship between Aβ deposition and NFT formation, transgenic mice with wild type and mutant human MAPT were created. In human, the MAPT gene is alternatively spliced to generate six different transcripts.…”

supporting

confidence: 61%

Genetics of Early-Onset Alzheimer Dementia

Rademakers

Cruts

Broeckhoven

2003

The Scientific World JOURNAL

View full text Add to dashboard Cite

Alzheimer's dementia (AD) is the most common degenerative disorder of the central nervous system. Although the onset of dementia is above 65 years of age in the majority of the patients (late-onset AD, LOAD), a small subgroup of patients develops AD before 65 years of age (early-onset AD, EOAD). To date 3 genes responsible for EOAD have been identified: the amyloid precursor protein gene (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). PSEN1 is the most frequently mutated EOAD gene with a mutation frequency of 18 to 50% in autosomal dominant EOAD. In addition, the ε4 allele of the gene encoding apolipoprotein E (APOE) was identified as a risk factor for both LOAD and EOAD. Many studies reported other susceptibility genes, but the APOE 4 alelle has been the only risk factor that was consistently replicated in all AD populations. Extensive cell biology research in the past ten years led to the hypothesis that the 4 EOAD genes lead to AD through a common biological pathway resulting in abnormal APP processing by subtle different mechanisms. Now, transgenic mice are produced to study the influence of EOAD mutations in vivo, eventually leading to the development of novel therapeutic strategies. KEYWORDS:Alzheimer dementia, neurodegeneration, mutations, linkage analysis, association analysis, mouse models DOMAINS: genetics (man), aging, neuroscience INTRODUCTIONAlzheimer's disease (AD) is a degenerative disorder of the central nervous system that causes progressive memory loss and cognitive decline during mid to late adult life, leading to dementia and ultimately death. AD is the most common form of dementia in the elderly, and represents the fourth largest cause of death in the developed world. In the near future, the impact of AD on our society will dramatically increase since, as populations live longer, the number of elderly people continues to grow.The clinical symptoms of AD display a substantial overlap with clinical symptoms observed in other neurodegenerative disorders with dementia as accompanying feature, such as *Corresponding author. Address: Department of Molecular Genetics (VIB8), Neurogenetics Group, University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium; Tel: +32 3 8202601/Fax: +32 3 8202541 ©2003 with author.497 Rademakers et al.: Genetics of Early-Onset Alzheimer Dementia TheScientificWorldJOURNAL (2003) 3, 497-519 frontotemporal dementia (FTD) and Creutzfeldt Jacob's disease (CJD). Therefore a definite diagnosis of AD can only be obtained at autopsy. Extensive neuronal loss, and two particular brain lesions in the cerebral cortex, hippocampus, and amygdala characterize AD: the senile plaques (SPs) and neurofibrillary tangles (NFTs). The SPs are compact extracellular deposits that consist of a large amyloid β (Aβ) core surrounded by dystrophic neurites. NFTs are intraneuronal inclusions of paired helical filaments (PHF) that are mainly composed of hyperphosphorylated microtubule associated protein tau (MAPT).Based on the age at which the first clinical symptoms become...

show abstract

“…[15][16][17] Similar to the results obtained with reduced Aph-1a expression, knockdown or knockout of either of the g-secretase components PS1, Nct or PEN-2 in the mouse led to affected levels of most of the nonsilenced g-secretase subunits. [18][19][20][21][22][23][24] In contrast, ablation of mouse PS2 expression had little effect on the expression levels of the other g-secretase components, 20,24,25 comparable to what we have observed in the I/I, II/II and III/III rat lines concerning the effect of reduced Aph-1b expression. 7 These findings suggest that PS2 and Aph-1b are somehow related.…”

Section: Discussionsupporting

confidence: 83%

“…16,21,22,24,38,39 Conversely, preventing mouse PS2 or Aph-1b expression did not affect or only slightly decreased g-secretase activity, respectively, and gave only a mild phenotype, whereas removal of PS1, Nct or Aph-1a is lethal. 16,25 We, therefore, hypothesize that the functioning of the PS2-and Aph-1b-containing g-secretase complex is different from that of the complexes with other subunit compositions.…”

Section: Discussionmentioning

confidence: 99%

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

et al. 2006

View full text Add to dashboard Cite

Selectively bred apomorphine susceptible (APO-SUS) rats display a complex behavioral phenotype remarkably similar to that of human neurodevelopmental disorders, such as schizophrenia. We recently found that the APO-SUS rats have only one or two Aph-1b gene copies (I/I and II/II rats, respectively), whereas their phenotypic counterpart has three copies (III/III). Aph-1b is a component of the c-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. Nevertheless, surprisingly little is known about csecretase expression during development. Here, we performed a longitudinal quantitative PCR study in embryos and the hippocampus of I/I, II/II and III/III rats, and found gene-dosage dependent differences in Aph-1b, but not Aph-1a, mRNA expression throughout pre-and postnatal development. On the basis of the developmental mRNA profiles, we assigned relative activities to the various Aph-1a and -1b gene promoters. Furthermore, in the three rat lines, we observed both tissue-specific and temporal alterations in c-secretase cleavage activity towards one of its best-known substrates, the amyloid-b precursor protein APP. We conclude that the low levels of Aph-1b mRNA and c-secretase activity observed in the I/I and II/II rats during the entire developmental period may well underlie their complex phenotype.

show abstract

Presenilin 2 deficiency causes a mild pulmonary phenotype and no changes in amyloid precursor protein processing but enhances the embryonic lethal phenotype of presenilin 1 deficiency

Cited by 482 publications

References 43 publications

Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells

Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells

Genetics of Early-Onset Alzheimer Dementia

Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

Contact Info

Product

Resources

About