Presenilin 2 Is the Predominant γ-Secretase in Microglia and Modulates Cytokine Release

Jayadev, Suman; Case, Amanda; Eastman, Alison J.; Nguyen, Huy; Pollak, Julia; Wiley, Jesse C.; Möller, Thomas; Morrison, Richard S.; Garden, Gwenn A.

doi:10.1371/journal.pone.0015743

Cited by 57 publications

(52 citation statements)

References 70 publications

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“…In corroboration of our findings, recent reports have shown that PS2 ␥-secretase cleaved more APP than PS1 ␥-secretase in microglia cells, regardless of the presence of PS1 (31). Thus, when studying ␥-secretase activity, we should consider the concentration of PS in the active ␥-secretase complex, which may aid in clarifying the pathogenesis of FAD caused by PS loss-of-function FAD mutations.…”

Section: Discussionsupporting

confidence: 90%

Comparison of Presenilin 1 and Presenilin 2 γ-Secretase Activities Using a Yeast Reconstitution System

Yonemura

Futai

Yagishita

et al. 2011

Journal of Biological Chemistry

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␥-Secretase is composed of at least four proteins, presenilin (PS), nicastrin (NCT), Aph1, and Pen2. PS is the catalytic subunit of the ␥-secretase complex, having aspartic protease activity. PS has two homologs, namely, PS1 and PS2. To compare the activity of these complexes containing different PSs, we reconstituted them in yeast, which lacks ␥-secretase homologs. Yeast cells were transformed with PS1 or PS2, NCT, Pen2, Aph1, and artificial substrate C55-Gal4p. After substrate cleavage, Gal4p translocates to the nucleus and activates transcription of the reporter genes ADE2, HIS3, and lacZ. ␥-Secretase activity was measured based on yeast growth on selective media and ␤-galactosidase activity. PS1 ␥-secretase was ϳ24-fold more active than PS2 ␥-secretase in the ␤-galactosidase assay. Using yeast microsomes containing ␥-secretase and C55, we compared the concentration of A␤ generated by PS1 or PS2 ␥-secretase. PS1 ␥-secretase produced ϳ24-fold more A␤ than PS2 ␥-secretase. We found the optimal pH of A␤ production by PS2 to be 7.0, as for PS1, and that the PS2 complex included immature NCT, unlike the PS1 complex, which included mature NCT. In this study, we compared the activity of PS1 or PS2 per one ␥-secretase complex. Co-immunoprecipitation experiments using yeast microsomes showed that PS1 concentrations in the ␥-secretase complex were ϳ28 times higher than that of PS2. Our data suggest that the PS1 complex is only marginally less active than the PS2 complex in A␤ production.␥-Secretase consists of at least four subunits, presenilin (PS), 3 nicastrin (NCT), anterior pharynx defective 1 (Aph1), and presenilin enhancer 2 (Pen2) (1). PS is the catalytic subunit of ␥-secretase with aspartic protease activity (2, 3). Amyloid-␤ (A␤) peptide, which plays a causative role in Alzheimer disease (AD), is produced after sequential cleavage of amyloid-␤ precursor protein (APP) by ␤-secretase and ␥-secretase. The A␤ mainly consists of A␤40 and A␤42 containing 40 and 42 amino acids, respectively. A␤42 is more prone to aggregation (4) and more toxic to neuronal cells. Many studies have reported that familial AD (FAD) mutations in PS and APP result in increased ratios of A␤42 to A␤40. The high A␤42 ratio is believed to lead to AD.PS has two homologs, namely, PS1 and PS2 (67% identical at the amino acid level). Aph1 also has two homologs: Aph1a (with alternative splicing variants Aph1a-S and a-L) and Aph1b. Sato et al. (5) reported that ␥-secretase contained only one of each subunit, and as such, six distinct ␥-secretases exist. Indeed, both PS1 and PS2 form a ␥-secretase complex with the other subunits, producing A␤ (6). ␥-Secretase cleaves many type I transmembrane proteins including APP and Notch, but the mechanism by which the different ␥-secretases select their substrates is unclear. These different ␥-secretases may have different functions and substrate selectivity.Ubiquitous expression of PS1 and PS2 mRNAs in many human and mouse tissues has been reported, with varying expression levels across their tissues and during...

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Section: Discussionsupporting

confidence: 90%

Comparison of Presenilin 1 and Presenilin 2 γ-Secretase Activities Using a Yeast Reconstitution System

Yonemura

Futai

Yagishita

et al. 2011

Journal of Biological Chemistry

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“…PS1 and PS2 have overlapping functions and are required for development and adult brain functions (Wines-Samuelson and Shen, 2005;Ho and Shen, 2011). The presenilin-1 (PS1) knock-out (KO) mice show perinatal lethality and impaired neural development (Shen et al, 1997;Handler et al, 2000;WinesSamuelson et al, 2005), whereas PS2 KO mice have little detectable phenotypes (Steiner et al, 1999), but PS1/2 double KO mice exhibit more severe phenotypes and die at embryonic day 9 (Donoviel et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…PSEN mutations confer partial loss of its presenilin function, and some mutations result in complete loss of its activity (Levitan et al, 1996;Song et al, 1999;Moehlmann et al, 2002;Seidner et al, 2006;Heilig et al, 2010). These findings together with striking age-dependent neurodegeneration observed in PS cDKO mice suggested that PSEN mutations might lead to AD as a result of partial loss of PS essential functions (Shen and Kelleher, 2007).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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Mutations in the presenilin (PSEN1 and PSEN2) genes are linked to familial Alzheimer's disease (AD) and cause loss of its essential function. Complete inactivation of presenilins in excitatory neurons of the adult mouse cerebral cortex results in progressive memory impairment and age-dependent neurodegeneration, recapitulating key features of AD. In this study, we examine the effects of varying presenilin dosage on cortical neuron survival by generating presenilin-1 conditional knock-out (PS1 cKO) mice carrying two, one, or zero copies of the PS2 gene. We found that PS1 cKO;PS2 ϩ/Ϫ mice at 16 months exhibit marked neurodegeneration in the cerebral cortex with ϳ17% reduction of cortical volume and neuron number, as well as astrogliosis and microgliosis compared with ϳ50% reduction of cortical volume and neuron number in PS1 cKO;PS2 Ϫ/Ϫ mice. Moreover, there are more apoptotic neurons labeled by activated caspase-3 immunoreactivity and TUNEL assay in PS1 cKO;PS2 ϩ/Ϫ mice at 16 months, whereas apoptotic neurons are increased in the PS1 cKO; PS2 Ϫ / Ϫ cerebral cortex at 4 months. The accumulation of the C-terminal fragments of the amyloid precursor protein is inversely correlated with PS dosage. Interestingly, levels of PS2 are higher in the cerebral cortex of PS1 cKO mice, suggesting a compensatory upregulation that may provide protection against neurodegeneration in these mice. Together, our findings show that partial to complete loss of presenilin activity causes progressively more severe neurodegeneration in the mouse cerebral cortex during aging, suggesting that impaired presenilin function by PSEN mutations may lead to neurodegeneration and dementia in AD.

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“…Brain samples from embryonic day 15 Psen1, and postnatal day 11 Psen2 KO mice were provided by Dr. Strooper (13) and Jayadev et al (26), respectively.…”

Section: Mouse Strains-tg-a246epsen1mentioning

confidence: 99%

Presenilins Regulate Neurotrypsin Gene Expression and Neurotrypsin-dependent Agrin Cleavage via Cyclic AMP Response Element-binding Protein (CREB) Modulation

Almenar-Queralt

Kim

Benner

et al. 2013

Journal of Biological Chemistry

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Background: Presenilins regulate multiple cellular pathways by controlling transcription. Results: Presenilins repress neurotrypsin expression by preventing CREB recruitment to its promoter. Conclusion: A new strategy utilized by presenilins to regulate CREB signaling relies on preventing CREB recruitment to gene promoters. Significance: Learning how presenilins control CREB signaling will help understanding their physiological/pathological roles.

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Presenilin 2 Is the Predominant γ-Secretase in Microglia and Modulates Cytokine Release

Cited by 57 publications

References 70 publications

Comparison of Presenilin 1 and Presenilin 2 γ-Secretase Activities Using a Yeast Reconstitution System

Comparison of Presenilin 1 and Presenilin 2 γ-Secretase Activities Using a Yeast Reconstitution System

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

Presenilins Regulate Neurotrypsin Gene Expression and Neurotrypsin-dependent Agrin Cleavage via Cyclic AMP Response Element-binding Protein (CREB) Modulation

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