Aβ induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597–624)

Shaked, Gideon M.; Kummer, Markus P.; Lu, Daniel C.; Galván, Verónica; Bredesen, Dale E.; Koo, Edward H.

doi:10.1096/fj.05-5032fje

Cited by 126 publications

(136 citation statements)

References 44 publications

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“…Besides its role in A␤ peptide generation, APP protein is required for synaptic plasticity and other neuronal functions (Dawson et al, 1999;Priller et al, 2006). Moreover A␤ oligomers bind to the cognate A␤ extracellular domain of APP and generate a G protein-dependent intracellular signaling pathway through APP dimerization (Shaked et al, 2006(Shaked et al, , 2009. These data suggest that modifications of APP expression and/or processing could be involved in the cPLA 2 inhibition-mediated protection against A␤ oligomers neurotoxicity.…”

Section: Discussionmentioning

confidence: 98%

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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Soluble beta-amyloid (A␤) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that A␤ oligomers activate cytosolic phospholipase A 2 (cPLA 2 ), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA 2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of A␤ oligomers in wild type mice. We further demonstrated that the A␤ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA 2 Ϫ/Ϫ mice. Interestingly, expression of the A␤ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA 2 Ϫ/Ϫ mice, but the relationship with the resistance of these mice to the A␤ oligomer toxicity requires further investigation. These results therefore show that cPLA 2 plays a key role in the A␤ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 98%

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Desbène

Malaplate-Armand

Youssef

et al. 2012

Neurobiology of Aging

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“…We recently showed [7,32] that a significant component of Aβ toxicity in vivo may be dependent on the cleavage of APP at Asp664, since transgenic mice otherwise identical to a well-characterized model of AD, PDAPP mice [13,27], but carrying a mutation that obliterates the Asp664 cleavage site in APP [PDAPP(D664A)mice] continue to produce and deposit Aβ, but do not develop AD-like deficits. One potential link between Aβ production and APP Asp664 cleavage has been described, with the demonstration that Aβ binds APP and induces APP multimerization [2,19,21,22,34,35], leading in turn to cleavage of the APP cytosolic tail at Asp664 [21,22,34], followed by synaptic and neuronal damage [22,34].…”

Section: Introductionmentioning

confidence: 99%

Long-term prevention of Alzheimer's disease-like behavioral deficits in PDAPP mice carrying a mutation in Asp664

Galván

Zhang

Gorostiza

et al. 2008

Behavioural Brain Research

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The deficits of Alzheimer's disease (AD) are believed to result, at least in part, from neurotoxicity of β-amyloid (Aβ), a set of 38-43 amino acid fragments derived from the β-amyloid precursor protein (APP). In addition, APP generates the APP-C31 and Jcasp toxic fragments intracellularly by cleavage at Asp664. We reported that mutation of Asp664 to A in a FAD-human APP transgene prevented AD-like deficits but did not affect Aβ production or deposition in PDAPP mice, arguing that D664A plays a crucial role in the generation of AD-like deficits. Whether D664A simply delays or completely prevents AD-like deficits, however, remained undefined. To address this question, we performed behavioral studies longitudinally on a pretrained mouse cohort at 9 and 13 months of age. While behavioral deficits were present in PDAPP mice, performance of Tg PDAPP(D664A) mice was not significantly different from non-Tg littermates' across all ages tested. Moreover, aberrant patterns in non-cognitive components of behavior in PDAPP mice were ameliorated in PDAPP(D664A) animals as well. A trend towards poorer retention at 9 mo and poorer learning at 13 mo that did not reach statistical significance was observed in PDAPP(D664A) mice. These results support and extend recent studies showing that cleavage of APP at Asp664 (or protein-protein interactions dependent on Asp664) is a crucial event in the generation of AD-like deficits in PDAPP mice. Our results thus further demonstrate that the D664A mutation either completely precludes, or markedly delays (beyond 13 mo) the appearance of AD-like deficits in this mouse model of AD.

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“…In the latter domain the dimerization appears to be mediated by the GXXXG motif near the luminal face of the transmembrane region (21, 23). In addition to promoting cell adhesion, APP dimerization has been proposed to increase susceptibility to cell death (20,24).Interestingly, by introducing cysteine mutations into the APP juxtamembrane region, it was shown that stable dimers through formation of these disulfide linkages result in significantly enhanced A␤ production (25). This finding is consistent with the observation that stable A␤ dimers are found intracellularly in neurons and in vivo in brain (26).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…In vivo interaction of APP, APLP1, and APLP2 was demonstrated by cross-linking studies from brain homogenates (18). To date at least four domains have been reported to promote APP dimerization; that is, the E1 domain containing the N-terminal growth factor-like domain and copper binding domain (17), the E2 domain containing the carbohydrate domain in the APP ectodomain (19), the APP juxtamembrane region (20), and the transmembrane domain (21,22). In the latter domain the dimerization appears to be mediated by the GXXXG motif near the luminal face of the transmembrane region (21,23).…”

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confidence: 99%

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Induced Dimerization of the Amyloid Precursor Protein Leads to Decreased Amyloid-β Protein Production

Eggert

Midthune

Cottrell

et al. 2009

Journal of Biological Chemistry

142

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The amyloid precursor protein (APP) plays a central role in Alzheimer disease (AD) pathogenesis because sequential cleavages by ␤-and ␥-secretase lead to the generation of the amyloid-␤ (A␤) peptide, a key constituent in the amyloid plaques present in brains of AD individuals. In several studies APP has recently been shown to form homodimers, and this event appears to influence A␤ generation. However, these studies have relied on APP mutations within the A␤ sequence itself that may affect APP processing by interfering with secretase cleavages independent of dimerization. Therefore, the impact of APP dimerization on A␤ production remains unclear. To address this question, we compared the approach of constitutive cysteine-induced APP dimerization with a regulatable dimerization system that does not require the introduction of mutations within the A␤ sequence. To this end we generated an APP chimeric molecule by fusing a domain of the FK506-binding protein (FKBP) to the C terminus of APP. The addition of the synthetic membrane-permeant drug AP20187 induces rapid dimerization of the APP-FKBP chimera. Using this system we were able to induce up to 70% APP dimers. Our results showed that controlled homodimerization of APP-FKBP leads to a 50% reduction in total A␤ levels in transfected N2a cells. Similar results were obtained with the direct precursor of ␤-secretase cleavage, C99/SPA4CT-FKBP. Furthermore, there was no modulation of different A␤ peptide species after APP dimerization in this system. Taken together, our results suggest that APP dimerization can directly affect ␥-secretase processing and that dimerization is not required for A␤ production.The mechanism of ␤-amyloid protein (A␤) 2 generation from the amyloid precursor protein is of major interest in Alzheimer disease research because A␤ is the major constituent of senile plaques, one of the neuropathological hallmarks of Alzheimer disease (1, 2). In the amyloidogenic pathway A␤ is released from the amyloid precursor protein (APP) (3) after sequential cleavages by ␤-secretase BACE1 (4 -6) and by the ␥-secretase complex (7,8). BACE1 cleavage releases the large ectodomain of APP while generating the membrane-anchored C-terminal APP fragment (CTF) of 99 amino acids (C99). Cleavage of ␤-CTF by ␥-secretase leads to the secretion of A␤ peptides of various lengths and the release of the APP intracellular domain (AICD) into the cytosol (9 -11). The ␥-secretase complex consists of at least four proteins: presenilin, nicastrin, Aph-I, and Pen-2 (12). Presenilin is thought to be the catalytic subunit of the enzyme complex (13), but how the intramembrane scission is carried out remains to be elucidated. Alternatively, APP can first be cleaved in the non-amyloidogenic pathway by ␣-secretase within the A␤ domain between Lys-16 and 15). This cleavage releases the APP ectodomain (APPs␣) while generating the membrane-bound C-terminal fragment (␣-CTF) of 83 amino acids (C83). The latter can be further processed by the ␥-secretase complex, resulting in the secretion of the sm...

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Aβ induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597–624)

Cited by 126 publications

References 44 publications

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit

Long-term prevention of Alzheimer's disease-like behavioral deficits in PDAPP mice carrying a mutation in Asp664

Induced Dimerization of the Amyloid Precursor Protein Leads to Decreased Amyloid-β Protein Production

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