Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein

Cordy, Joanna M.; Hussain, Ishrut; Dingwall, Colin; Hooper, Nigel M.; Turner, Anthony J.

doi:10.1073/pnas.1635130100

Cited by 341 publications

(294 citation statements)

References 37 publications

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“…Cholesterol levels are thought to modulate the processing of amyloid precursor protein by controlling secretase activity. Current evidence suggests that α-secretase resides in phospholipid-rich domains, while γ and β-secretases are found in lipid rafts (Riddell et al 2001;Wahrle et al 2002;Cordy et al 2003). Experimentally reducing cholesterol in tissue culture has been shown to enhance α-secretase activity and to inhibit γ-secretase activity and reduce the production of pathogenic forms of Aβ (Bodovitz and Klein 1996;Kojro et al 2001;Ehehalt et al 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Experimentally reducing cholesterol in tissue culture has been shown to enhance α-secretase activity and to inhibit γ-secretase activity and reduce the production of pathogenic forms of Aβ (Bodovitz and Klein 1996;Kojro et al 2001;Ehehalt et al 2003). Use of a glycosylphosphatidylinositol (GPI) anchor to target β-secretase to lipid rafts increased Aβ formation, and this amyloidogenic effect was inhibited when lipid rafts were disrupted by depleting cholesterol from the membrane (Cordy et al 2003). Nonetheless, there have been reports that lowering cholesterol increases Aβ production (Abad-Rodriguez et al 2004), suggesting that maintaining homeostatic levels of cholesterol in brain may be important for normal neuronal function.…”

Section: Discussionmentioning

confidence: 99%

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ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

Bandaru

Troncoso

Wheeler

et al. 2009

Neurobiology of Aging

129

106

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The ε4 allele of ApoE is associated with an earlier onset and faster progression of Alzheimer's disease in patients with the familial form of this neurodegenerative condition. Although ApoE4 has been repeatedly associated with altered sphingomyelin and cholesterol levels in tissue culture and rodent models, there has not been a direct quantification of sphingomyelin or sterol levels in the brains of patients with different forms of ApoE. We measured the sphingolipid and sterol content of human brain tissues and found no evidence of perturbed sterol or sphingolipid biochemistry in the brains of individuals expressing ApoE4 who did not have a preexisting neurodegenerative condition. Nevertheless, ApoE4 was associated with gross abnormalities in the sterol and sphingolipid content of numerous brain regions in patients with Alzheimer's diseease. The findings suggest that ApoE4 may not by itself alter sterol or sphingolipid metabolism in the brain under normal conditions, but that other neuropathologic changes of Alzheimer's are required to unmask the effect of ApoE4, and to perturb sterol and sphingolipid biochemistry.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

Bandaru

Troncoso

Wheeler

et al. 2009

Neurobiology of Aging

129

106

View full text Add to dashboard Cite

show abstract

“…Surprisingly, the propeptide seems not to significantly affect BACE1 proteolytic function (Creemers et al 2001). BACE1 reaches the PM and becomes enriched in lipid rafts (Riddell et al 2001;Cordy et al 2003). Rafts are discussed as potential sites for efficient Ab generation, as APP and BACE1 apparently come into immediate contact within this compartment (Ehehalt et al 2003; Abad- Whether b-and g-secretase are transported together is not known.…”

Section: Subcellular Sites Of App Processingmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

871

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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“…We determined that APP 770 1 and APP 695 were each expressed in SH-SY5Y cells and migrated in 7.5% polyacrylamide SDS gels to positions corresponding to ϳ148 and ϳ120 kDa, respectively, based upon previously published data (Buxbaum et al, 1990(Buxbaum et al, , 1998Cordy et al, 2003). Antibody APP369 (a gift from Sam Gandy, Thomas Jefferson University, Philadelphia, PA) is a rabbit polyclonal raised against the C terminus of APP, and it was used for immunofluorescent staining of APP.…”

Section: Antibodies Plasmids and Lentivirusesmentioning

confidence: 99%

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

Shrivastava-Ranjan

Faúndez

Fang

et al. 2008

MBoC

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␤-Amyloid peptides (A␤) are the major component of plaques in brains of Alzheimer's patients, and are they derived from the proteolytic processing of the ␤-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated, and it is tightly connected to its processing by secretases. We proposed previously that transport of APP within the cell is mediated in part through its sorting into Mint/X11-containing carriers. To test our hypothesis, we purified APP-containing vesicles from human neuroblastoma SH-SY5Y cells, and we showed that Mint2/3 are specifically enriched and that Mint3 and APP are present in the same vesicles. Increasing cellular APP levels increased the amounts of both APP and Mint3 in purified vesicles. Additional evidence supporting an obligate role for Mint3 in traffic of APP from the trans-Golgi network to the plasma membrane include the observations that depletion of Mint3 by small interference RNA (siRNA) or mutation of the Mint binding domain of APP changes the export route of APP from the basolateral to the endosomal/lysosomal sorting route. Finally, we show that increased expression of Mint3 decreased and siRNA-mediated knockdowns increased the secretion of the neurotoxic ␤-amyloid peptide, A␤ 1-40 . Together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic. INTRODUCTIONThe hallmark of Alzheimer's disease is the presence in brain of plaques that contain A␤ peptides, formed by the result of proteolytic processing of the ␤-amyloid precursor protein (APP). APP is a ubiquitous, single-pass transmembrane protein of unknown function that is highly expressed in brain. Processing involves the sequential actions of ␣-or ␤-plus ␥-secretases, each of which are found in multiple cellular locations (Kuentzel et al., 1993;Selkoe, 1998;Yan et al., 2001). Although processing may occur at any step, the trans-Golgi network (TGN) is the earliest site at which APP processing is thought to commence, and APP is internalized from the cell surface to endosomal compartments where ␥-secretase also acts (Selkoe et al., 1996;Greenfield et al., 1999;Lah and Levey, 2000;Bagshaw et al., 2003).The C-terminal domain of APP contains the tyrosinebased sorting motif, YENPTY, which is conserved across species and a determinant of APP traffic (Perez et al., 1999;Bonifacino and Traub, 2003;King et al., 2004). Such sorting motifs function by binding specific adaptors to facilitate their selective import into budding carriers and ensure specificity in cargo selection and coat recruitment. The highly conserved phosphotyrosine binding (PTB) domains in all three Mint proteins have been shown previously to bind directly to the YENPXY motif of APP (Borg et al., 1996(Borg et al., , 1998Zhang et al., 1997;Sastre et al., 1998;Tanahashi and Tabira, 1999;Tomita et al., 1999;Ho et al., 2002;Araki et al., 2003). Other PTB domain containing proteins have similarly been shown to bind APP, including the Fe65 (Sabo et al., 1999) family, Dab2 (Howell et al., 1999), JIP1b (King et al....

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Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein

Cited by 341 publications

References 37 publications

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

Trafficking and Proteolytic Processing of APP

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

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