Contrasting Role of Presenilin-1 and Presenilin-2 in Neuronal Differentiation<i>In Vitro</i>

Hong, Chang‐Sook; Caromile, Leslie A.; Nomata, Yasuhiro; Mori, Hiroshi; Bredesen, Dale E.; Koo, Edward H.

doi:10.1523/jneurosci.19-02-00637.1999

Cited by 57 publications

(35 citation statements)

References 37 publications

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“…By contrast, PS1 appears to protect neurons against etoposide and staurosporine-induced apoptosis (62). This antiapoptotic function of PS1 agrees well with a recent work showing that NT2 cells expressing PS1 antisense cDNA displayed increased apoptosis and could be rescued by the antiapoptotic oncogene bcl-2 (63). Overall, these studies underline the fact that PS1 and PS2 most likely display distinct abilities to control programmed cell death.…”

Section: Role Of Ps In Programmed Cell Deathsupporting

confidence: 89%

Presenilins: Multifunctional Proteins Involved in Alzheimer's Disease Pathology

Checler

1999

IUBMB Life

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Section: Role Of Ps In Programmed Cell Deathsupporting

confidence: 89%

Presenilins: Multifunctional Proteins Involved in Alzheimer's Disease Pathology

Checler

1999

IUBMB Life

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“…Data from animal models show that PS1 deficiency results in perinatal death (Shen et al, 1997;Wong et al, 1997) with neuronal loss prominent on embryonic days 17-18 (Shen et al, 1997) and that conditional inactivation of both presenilins in the adult forebrain results in age-dependent neurodegeneration (Saura et al, 2004) tissue shrinkage and apoptosis (Feng et al, 2004). Furthermore, downregulation of PS1 in NT2 cells induces apoptosis (Hong et al, 1999), and primary neuronal cultures from PS1 null embryos show increased vulnerability to oxidative stress (Nakajima et al, 2001). The current study provides evidence that the neuroprotective role of PS1 depends on its ability to promote PI3K/Akt signaling, a cellular pathway critical to cell survival (Datta et al, 1999;Brunet et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Baki

Neve²,

Shao³

et al. 2008

J. Neurosci.

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The role of presenilin-1 (PS1) in neuronal phosphatidylinositol 3-kinase (PI3K)/Akt signaling was investigated in primary neuronal cultures from wild-type (WT) and PS1 null (PS1؊/؊) embryonic mouse brains. Here we show that in PS1Ϫ/Ϫ cultures, the onset of neuronal maturation coincides with a decrease in the PI3K-dependent phosphorylation-activation of Akt and phosphorylationinactivation of glycogen synthase kinase-3 (GSK-3). Mature PS1Ϫ/Ϫ neurons show increased activation of apoptotic caspase-3 and progressive degeneration preceded by dendritic retraction. Expression of exogenous WT PS1 or constitutively active Akt in PS1Ϫ/Ϫ neurons stimulates PI3K signaling and suppresses both caspase-3 activity and dendrite retraction. The survival effects of PS1 are sensitive to inhibitors of PI3K kinase but insensitive to ␥-secretase inhibitors. Familial Alzheimer disease (FAD) mutations suppress the ability of PS1 to promote PI3K/AKT signaling, prevent phosphorylation/inactivation of GSK-3 and promote activation of caspase-3. These mutation effects are reversed upon coexpression of constitutively active Akt. Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.

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“…Retinoic acid (RA), the active metabolite of vitamin A (retinoid), has been shown to control the expression of genes related to APP processing (Lahiri et al, 1995;Yang et al, 1998;Hong et al, 1999;Culvenor et al, 2000;Satoh and Kuroda, 2000). RA regulates gene expression through its nuclear receptors: the RA receptors (RARs) and retinoid X receptors (RXRs) (Mangelsdorf and Evans, 1995).…”

Section: Introductionmentioning

confidence: 99%

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

Ding¹,

et al. 2008

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Recent studies have revealed that disruption of vitamin A signaling observed in Alzheimer's disease (AD) leads to ␤-amyloid (A␤) accumulation and memory deficits in rodents. The aim of the present study was to evaluate the therapeutic effect of all-trans retinoic acid (ATRA), an active metabolite of vitamin A, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice, a well established AD mouse model. Here we report a robust decrease in brain A␤ deposition and tau phosphorylation in the blinded study of APP/PS1 transgenic mice treated intraperitoneally for 8 weeks with ATRA (20 mg/kg, three times weekly, initiated when the mice were 5 months old). This was accompanied by a significant decrease in the APP phosphorylation and processing. The activity of cyclin-dependent kinase 5, a major kinase involved in both APP and tau phosphorylation, was markedly downregulated by ATRA treatment. The ATRA-treated APP/PS1 mice showed decreased activation of microglia and astrocytes, attenuated neuronal degeneration, and improved spatial learning and memory compared with the vehicle-treated APP/ PS1 mice. These results support ATRA as an effective therapeutic agent for the prevention and treatment of AD.

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Contrasting Role of Presenilin-1 and Presenilin-2 in Neuronal DifferentiationIn Vitro

Cited by 57 publications

References 37 publications

Presenilins: Multifunctional Proteins Involved in Alzheimer's Disease Pathology

Presenilins: Multifunctional Proteins Involved in Alzheimer's Disease Pathology

Wild-Type But Not FAD Mutant Presenilin-1 Prevents Neuronal Degeneration by Promoting Phosphatidylinositol 3-Kinase Neuroprotective Signaling

Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model

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