Differential Regulation of APP Secretion by Apolipoprotein E3 and E4

Wolozin, Benjamin; Basaric-Keys, Jasna; Canter, Robert J.; Li, Yunhua; Strickland, Dudley K.; Sunderland, Trey

doi:10.1007/978-1-4899-0209-2_14

Cited by 4 publications

(6 citation statements)

References 16 publications

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“…We observed that ApoE4 was more effective than ApoE in the increase of APP endocytosis and decrease of s␣-APP. A previous report described ApoE3-increased and ApoE4-decreased s␣-APP in PC12 cells (Wolozin et al, 1996). Although PC12 is a neuronal cell line, the different ApoE4 effects could be derived from a difference in ApoER2 or X11␣/␤ level from that in N2a-APP cells.…”

Section: Discussionmentioning

confidence: 86%

Apolipoprotein Receptor 2 and X11α/β Mediate Apolipoprotein E-Induced Endocytosis of Amyloid-β Precursor Protein and β-Secretase, Leading to Amyloid-β Production

He¹,

Cooley²,

Chung³

et al. 2007

J. Neurosci.

103

105

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The homeostasis of amyloid-␤ (A␤) in the brain is critical to the pathogenesis of Alzheimer's disease (AD). A␤ is a fragment of amyloid-␤ precursor protein (APP) generated in neurons by two proteases, ␤-and ␥-secretases. APP and ␤-secretase, both present on cell surface, are endocytosed into endosomes to produce A␤. The molecular mechanism by which neurons trigger the production of A␤ is poorly understood. We describe here evidence that the binding of lipid-carrying apolipoprotein E (ApoE) to receptor apolipoprotein E receptor 2 (ApoER2) triggers the endocytosis of APP, ␤-secretase, and ApoER2 in neuroblastoma cells, leading to the production of A␤. This mechanism, mediated by adaptor protein X11␣ or X11␤ (X11␣/␤), whose PTB (phosphotyrosine-binding) domain binds to APP and a newly recognized motif in the cytosolic domain of ApoER2. Isomorphic form ApoE4 triggers the production of more A␤ than by ApoE2 or ApoE3; thus, it may play a role in the genetic risk of ApoE4 for the sporadic AD. The mechanism, which functions independently from Reelin-ApoER2 interaction, also provides a link between lipid uptake and A␤ production, which may be important for the regulation of neuronal activity.

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Section: Discussionmentioning

confidence: 86%

Apolipoprotein Receptor 2 and X11α/β Mediate Apolipoprotein E-Induced Endocytosis of Amyloid-β Precursor Protein and β-Secretase, Leading to Amyloid-β Production

He¹,

Cooley²,

Chung³

et al. 2007

J. Neurosci.

103

105

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“…The effects of apoE isoforms on APP metabolism have been investigated in several cell culture systems with inconsistent results on cellular APP and secreted sAPP and Aβ (Biere et al . 1995; Wolozin et al . 1996; Hass et al .…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, no published studies have measured Aβ40, Aβ42 or APP‐CTFs after the addition of exogenous purified apoE. Prior studies adding purified apoE to cells in culture only evaluated APP or sAPP (Wolozin et al . 1996; Hass et al .…”

Section: Discussionmentioning

confidence: 99%

“…The effects of apoE isoforms on APP metabolism have been investigated in several cell culture systems with inconsistent results on cellular APP and secreted sAPP and Ab (Biere et al 1995;Wolozin et al 1996;Hass et al 1998;Oron et al 2000;Cedazo-Minguez et al 2001;Vincent and Smith 2001). Surprisingly, no published studies have measured Ab40, Ab42 or APP-CTFs after the addition of exogenous purified apoE.…”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, no published studies have measured Ab40, Ab42 or APP-CTFs after the addition of exogenous purified apoE. Prior studies adding purified apoE to cells in culture only evaluated APP or sAPP (Wolozin et al 1996;Hass et al 1998;Oron et al 2000;Cedazo-Minguez et al 2001;Vincent and Smith 2001) and not Ab or APP-CTF. The most detailed study assessing the interaction of apoE with APP evaluated CHO cells and a human glioma cell line double transfected with apoE isoforms and APP695 (Biere et al 1995).…”

Section: Discussionmentioning

confidence: 99%

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Apolipoprotein E modulates γ‐secretase cleavage of the amyloid precursor protein

Irizarry¹,

Deng²,

Lleó³

et al. 2004

Journal of Neurochemistry

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Polymorphisms in the apolipoprotein E (APOE) gene affect the risk of Alzheimer disease and the amount of amyloid b-protein (Ab) deposited in the brain. The apoE protein reduces Ab levels in conditioned media from cells in culture, possibly through Ab clearance mechanisms. To explore this effect, we treated multiple neural and non-neural cell lines for 24 h with apoE at concentrations similar to those found in the cerebrospinal fluid (1-5 lg/mL). The apoE treatment reduced Ab40 by 60-80% and Ab42 to a lesser extent (20-30%) in the conditioned media. Surprisingly, apoE treatment resulted in an accumulation of amyloid precursor protein (APP)-C-terminal fragments in cell extracts and a marked reduction of APP intracellular domain-mediated signaling, consistent with diminished c-secretase processing of APP. All three isoforms of apoE, E2, E3 and E4, had similar effects on Ab and APP-Cterminal fragments, and the effects were independent of the low-density lipoprotein receptor family. Apolipoprotein E had minimal effects on Notch cleavage and signaling in cell-based assays. These data suggest that apoE reduces c-secretase cleavage of APP, lowering secreted Ab levels, with stronger effects on Ab40. The apoE modulation of Ab production and APP signaling is a potential mechanism affecting Alzheimer disease risk. Keywords: amyloid b-protein, amyloid precursor protein, apolipoprotein E, c-secretase. The apolipoprotein E (APOE) e4 allele is a genetic risk factor for sporadic Alzheimer disease (AD) (Rebeck et al. 1993;Saunders et al. 1993;Strittmatter et al. 1993); however, the mechanism of this increased risk is unclear. Apolipoprotein E in the CNS is implicated in repair, synaptogenesis, nerve growth and development (Mahley 1988;Poirier et al. 1993). Human studies indicate that the APOE e4 allele affects amyloid pathology, resulting in increased amyloid deposition in AD (Rebeck et al. 1993;Saunders et al. 1993) and increased brain levels of the amyloid b-protein (Ab) species ending at val-40 (Ab40) (Gearing et al. 1996;Ishii et al. 1997;Mann et al. 1997;McNamara et al. 1998). Apolipoprotein E colocalizes with amyloid plaques and apoE has been characterized as a 'pathological molecular chaperone', mediating b-pleated sheet formation of polypeptide fragments (Wisniewski and Frangione 1992). Studies of amyloid precursor protein (APP) transgenic mice lacking APOE support a role for apoE in affecting Ab fibril formation. Abbreviations used: Ab, amyloid b-protein; AD, Alzheimer disease; AICD, APP intracellular domain; apoE, apolipoprotein E; APP, amyloid precursor protein; CHO, Chinese hamster ovary; CTF, C-terminal fragment; E (141)149) 2, tandem double sequence containing amino acids 141-149 of the receptor-binding domain of apoE; HDL, high density lipoprotein; HEK, human embryonic kidney; LDL, low-density lipoprotein; LRP, LDL receptor-related protein; NDEC, construct containing Notch bp 5374-7836 lacking the extracellular domain but containing the membrane-spanning region, including the c-secretase cleavage site, and...

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Differential Regulation of APP Secretion by Apolipoprotein E3 and E4

Wolozin¹,

Basaric-Keys²,

Canter³

et al. 1996

Neurodegenerative Diseases

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The apolipoprotein E isozyme, apolipoprotein E4, has been implicated as a risk factor for Alzheimer's disease. One reason for the increased risk may be that apolipoprotein E binds to the A@ peptide, but there may be other factors as well. We show that apolipoprotein E is a potent regulator of the secretion of amyloid precursor protein. In cultures of PC12 cells, nanomolar levels of apolipoprotein E3 induce a rapid decrease in the secretion of APP, being observable in 30 min. and stable over 24 hours. Apolipoprotein E4, in contrast, increases secretion of APP over a similar time course. Reciprocal changes occur in cellular amyloid precursor protein. Differential characteristics are also seen in apo E binding to the cells, where apo E4 binds over a slower time course than apo E3. These results suggest a novel mechanism by which apolipoprotein E may be influencing the metabolism of amyloid precursor protein.

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Differential Regulation of APP Secretion by Apolipoprotein E3 and E4

Cited by 4 publications

References 16 publications

Apolipoprotein Receptor 2 and X11α/β Mediate Apolipoprotein E-Induced Endocytosis of Amyloid-β Precursor Protein and β-Secretase, Leading to Amyloid-β Production

Apolipoprotein Receptor 2 and X11α/β Mediate Apolipoprotein E-Induced Endocytosis of Amyloid-β Precursor Protein and β-Secretase, Leading to Amyloid-β Production

Apolipoprotein E modulates γ‐secretase cleavage of the amyloid precursor protein

Differential Regulation of APP Secretion by Apolipoprotein E3 and E4

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