Role of amyloid precursor protein (APP): Study with antisense transfection of human neuroblastoma cells

LeBlanc, Andréa C.; Kovacs, Dora M.; Chen, H. Y.; Villaré, F.; Tykocinski, Mark L.; Autilio-Gambetti, L.; Gambetti, Pierluigi

doi:10.1002/jnr.490310407

Cited by 95 publications

(52 citation statements)

References 56 publications

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“…As reported previously (23), the three APP isoforms are expressed in astrocytes with a predominant expression of APP 770 and APP 751 , whereas cortical neurons abundantly express APP 695 mRNA but only small amounts of APP 770 and APP 751 mRNAs (Fig. 2, A and C).…”

Section: Tgf-␤1 Potentiates Amyloid-␤ Generationsupporting

confidence: 83%

Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice

Lesné

Docagne

Gabriel

et al. 2003

Journal of Biological Chemistry

131

117

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Accumulation of the amyloid-␤ peptide (A␤) in the brain is crucial for development of Alzheimer's disease. Expression of transforming growth factor-␤1 (TGF-␤1), an immunosuppressive cytokine, has been correlated in vivo with A␤ accumulation in transgenic mice and recently with A␤ clearance by activated microglia. Here, we demonstrate that TGF-␤1 drives the production of A␤40/42 by astrocytes leading to A␤ production in TGF-␤1 transgenic mice. First, TGF-␤1 induces the overexpression of the amyloid precursor protein (APP) in astrocytes but not in neurons, involving a highly conserved TGF-␤1-responsive element in the 5-untranslated region (؉54/؉74) of the APP promoter. Second, we demonstrated an increased release of soluble APP-␤ which led to TGF-␤1-induced A␤ generation in both murine and human astrocytes. These results demonstrate that TGF-␤1 potentiates A␤ production in human astrocytes and may enhance the formation of plaques burden in the brain of Alzheimer's disease patients.

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Section: Tgf-␤1 Potentiates Amyloid-␤ Generationsupporting

confidence: 83%

Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice

Lesné

Docagne

Gabriel

et al. 2003

Journal of Biological Chemistry

131

117

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“…This construct has previously been used successfully to inhibit high levels of APP expression (35). The antisense construct did not induce cell death in the absence of Bax cDNA (Fig.…”

Section: Prp Protects Human Neurons Against Bax-mediated Cellmentioning

confidence: 99%

Prion Protein Protects Human Neurons against Bax-mediated Apoptosis

Bounhar

Zhang

Goodyer

et al. 2001

Journal of Biological Chemistry

339

271

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The function of the cellular prion protein (PrP) is still poorly understood. We present here an unprecedented role for PrP against Bax-mediated neuronal apoptosis and show that PrP potently inhibits Bax-induced cell death in human primary neurons. Deletion of four octapeptide repeats of PrP (PrP⌬OR) and familial D178N and T183A PrP mutations completely or partially eliminate the neuroprotective effect of PrP. PrP remains anti-apoptotic despite truncation of the glycosylphosphatidylinositol (GPI) anchor signal peptide, indicating that the neuroprotective form of PrP does not require the abundant cell surface GPI-anchored PrP. Our results implicate PrP as a potent and novel anti-apoptotic protein against Bax-mediated cell death.Prion protein (PrP) 1 is a sialoglycoprotein that is highly expressed in brain, heart, lungs, and lymphoid system and at lower levels in several other tissues such as muscle (1, 2). Mature PrP contains two N-linked glycans and a disulfide bond (reviewed in Ref.3). PrP possesses a C-terminal GPI-anchoring signal and a transmembrane domain that can generate type I ( Ctm PrP) or type II ( Ntm PrP) transmembrane-spanning isoforms in isolated endoplasmic reticulum microsomes or phospholiposomes (4 -7). In most cells, the majority of the PrP localizes to the cell surface as a GPI-anchored protein (8). The complete translocation of PrP is dependent on translocation accessory factors (TrAF). In the absence of TrAF, PrP is exclusively synthesized in a transmembrane topology (7).Whereas the role of the infectious form of PrP in a number of human and animal neurodegenerative diseases has been extensively studied, the normal function of PrP is still poorly understood. PrP-null mice display no dramatic phenotype (9). However, evidence indicates that PrP may promote sleep continuity (10). PrP is involved in the regulation of presynaptic copper concentration, intracellular calcium concentration, activation of lymphocytes, astrocyte proliferation, and signal transduction and has antioxidant properties (11-16). Although controversial, PrP-null mice are also found to be impaired in long term potentiation (17)(18)(19). In addition, it has been shown that PrP-null neuronal cell lines are more susceptible to serum deprivation-induced cell death and that Bcl-2 overexpression can attenuate the sensitivity of PrP-null neuronal cell lines to serum deprivation (20). Kurschner and Morgan (21, 22) reported that yeast PrP fusion proteins interact with Bcl-2. Furthermore, four identical N-terminal PrP octapeptide repeats (OR) that are highly conserved in evolution share limited similarity with the Bcl-2 homology domain 2 (BH2) of Bcl-2 proteins (23, 24). Bcl-2 proteins are central to the regulation of cell death, and the BH2 domain is crucial to the anti-apoptotic function of Bcl-2 and its interaction with the pro-apoptotic Bax protein (24,25). Based on these features of PrP, we hypothesized that similar to Bcl-2 family members, PrP may play a role in the regulation of neuronal apoptosis. In the present study, we have...

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“…APP has been shown to be involved in the growth regulation of different cell types (12,17). In cultured neurons, APP has been shown to be associated with the extracellular matrix (11) and to mediate cell-cell and cell-surface adhesion (4).…”

Section: Introductionmentioning

confidence: 99%

Chondroitin Sulfate Proteoglycans Are Associated with the Lesions of Alzheimer's Disease

DeWitt

Silver

Canning

et al. 1993

Experimental Neurology

175

107

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Chondroitin sulfate proteoglycans (CSPG) are extracellular matrix proteins inhibitory to neurite outgrowth in vitro and correlated with decreased neurite outgrowth after CNS injury. Previously, heparan sulfate proteoglycan and dermatan sulfate proteoglycan have been shown to be associated with senile plaques (SPs) and neurofibrillary tangles (NFTs) but CSPG was not. In an immunocytochemical study, three monoclonal antibodies to different sulfation states of the chondroitin glycosaminoglycan were used to localize CSPG in cases of Alzheimer's disease. Chondroitin 4-sulfate was found in both SPs and NFTs. An antibody to unsulfated chondroitin strongly immunostained intracellular NFTs and the dystrophic neurites of SPs. Chondroitin 6-sulfate was found in NFTs and the area around SPs. These results suggest that CSPG, in addition or as an alternative to ~-amyloid protein, could be responsible for the regression of neurites around senile plaques in Alzheimer's disease.

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Role of amyloid precursor protein (APP): Study with antisense transfection of human neuroblastoma cells

Cited by 95 publications

References 56 publications

Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice

Transforming Growth Factor-β1 Potentiates Amyloid-β Generation in Astrocytes and in Transgenic Mice

Prion Protein Protects Human Neurons against Bax-mediated Apoptosis

Chondroitin Sulfate Proteoglycans Are Associated with the Lesions of Alzheimer's Disease

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