A novel pathway for amyloid precursor protein processing

Portelius, Erik; Price, Eric A.; Brinkmalm, Gunnar; Stiteler, Mark; Olsson, Maria; Persson, Rita; Westman‐Brinkmalm, Ann; Zetterberg, Henrik; Simon, Adam J.; Blennow, Kaj

doi:10.1016/j.neurobiolaging.2009.06.002

Cited by 147 publications

(114 citation statements)

References 29 publications

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“…Due to its ability to cut APP at different positions, ␥-secretase yields A␤ peptides of different length. 18 The patients in this study had increased A␤ 42 :A␤ 40 and A␤ 42 :A␤ 38 ratios, demonstrating a shift of the cleavage site activity toward production of A␤ 42 . It has been proposed that the cleavage specificity might be influenced by membrane thickness 19 and different lipid species have different effects on ␥-secretase activity in vitro.…”

Section: Statistics Withmentioning

confidence: 58%

γ-Secretase-dependent amyloid-β is increased in Niemann-Pick type C

Mattsson

Zetterberg²,

Bianconi³

et al. 2011

Neurology

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Objective: Niemann-Pick disease type C (NPC) is an inherited disorder characterized by intracellular accumulation of lipids such as cholesterol and glycosphingolipids in endosomes and lysosomes. This accumulation induces progressive degeneration of the nervous system. NPC shows some intriguing similarities with Alzheimer disease (AD), including neurofibrillary tangles, but patients with NPC generally lack amyloid-␤ (A␤) plaques. Lipids affect ␥-secretase-dependent amyloid precursor protein (APP) metabolism that generates A␤ in vitro, but this has been difficult to prove in vivo. Our aim was to assess the effect of altered lipid constituents in neuronal membranes on amyloidogenic APP processing in humans. Methods:We examined A␤ in CSF from patients with NPC (n ϭ 38) and controls (n ϭ 14). CSF was analyzed for A␤ 38 , A␤ 40 , A␤ 42 , ␣-cleaved soluble APP, ␤-cleaved soluble APP, total-tau, and phospho-tau.Results: A␤ release was markedly increased in NPC, with a shift toward the A␤ 42 isoform. Levels of ␣-and ␤-cleaved soluble APP were similar in patients and controls. Patients with NPC had increased total-tau. Patients on treatment with miglustat (n ϭ 18), a glucosylceramide synthase blocker, had lower A␤ 42 and total-tau than untreated patients. Conclusion:Increased CSF levels of A␤ 38 , A␤ 40 , and A␤ 42 and unaltered levels of ␤-cleaved soluble APP are consistent with increased ␥-secretase-dependent A␤ release in the brains of patients with NPC. These results provide the first in vivo evidence that neuronal lipid accumulation facilitates ␥-secretase-dependent A␤ production in humans and may be of relevance to AD pathogenesis. Neurology Abnormal amyloid-␤ (A␤) metabolism is a core pathologic event in Alzheimer disease (AD).1 A␤ is released from the transmembrane protein A␤ precursor protein (APP) through cleavages by the enzymes ␤-secretase and ␥-secretase. A␤ metabolism has been linked to lipid homeostasis 2,3 and several studies suggest that ␥-secretase efficiency is affected by membrane lipid raft topography. [4][5][6][7] Evidence from humans of the effects of cellular cholesterol homeostasis on amyloid metabolism is lacking. To evaluate the effects of altered lipid constituents in neuronal membranes on APP processing in vivo, we examined A␤ in CSF from patients with Niemann-Pick type C disease (NPC).NPC is a lysosomal storage disorder resulting from mutations in the genes encoding for the NPC1 and NPC2 proteins. 8 The clinical spectrum is broad, but progressive neurologic impaire-Pub ahead of print on December 29, 2010, at www.neurology.org. References e1-e18 are available on the Neurology Web site at www.neurology.org.

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Section: Statistics Withmentioning

confidence: 58%

γ-Secretase-dependent amyloid-β is increased in Niemann-Pick type C

Mattsson

Zetterberg²,

Bianconi³

et al. 2011

Neurology

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“…Such data concur with our findings that APP is processed along two major product lines, the A␤40 product line resulting in the release of A␤40 and the A␤42 product line resulting in A␤42 and A␤38 as major forms. The reconstituted systems however fail to generate the shorter A␤ peptides, such as A␤30-A␤37, which are naturally occurring A␤ peptides present both in CSF and in cell culture media (22).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Intermediate Steps in Amyloid Beta (Aβ) Production under Near-native Conditions

Olsson

Schmidt

Althoff

et al. 2014

Journal of Biological Chemistry

109

113

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Background:The 42 amino acid long amyloid beta peptide (A␤42) plays a pivotal role in Alzheimer disease. Results: A novel assay was developed and enabled us to describe the process of 〈␤42 production and modulation. Conclusion: A␤42 is generated through different pathways, which are differently affected by disease causing mutations and anti-amyloidogenic drugs. Significance: The data provide key information for therapeutic development in Alzheimer disease.

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“…This attenuation may be due to a shift from ␤-cleavage to ␣-cleavage of APP, as the concurrent increase in sAPP␣ and decrease in sAPP␤ in the media were seen by ELISA (data not shown). Alternatively, enhanced cleavage of ␤-CTF by ␣-secretase could also be a possible explanation (Beher et al, 2002;Cook et al, 2010;Portelius et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic Mice

Mitani

Yarimizu²,

Saita³

et al. 2012

J. Neurosci.

179

189

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␥-Secretase inhibitors (GSIs) reduce amyloid-␤ (A␤) peptides but inevitably increase the ␤-C-terminal fragment (␤-CTFSubchronic dosing with either GSI rather impaired normal cognition in 3-month-old Tg2576 mice, with no inhibition on the processing of other ␥-secretase substrates, such as Notch, N-cadherin, or EphA4, in the brain. LY450139 also impaired normal cognition in wild-type mice; however, the potency was 10-fold lower than that in Tg2576 mice, indicating an APP-dependent mechanism likely with ␤-CTF accumulation. Immunofluorescence studies revealed that the ␤-CTF accumulation was localized in the presynaptic terminals of the hippocampal stratum lucidum and dentate hilus, implying an effect on presynaptic function in the mossy fibers. In contrast, both acute and subchronic dosing with GSM-2 significantly ameliorated memory deficits in Tg2576 mice and did not affect normal cognition in wild-type mice. We demonstrated a clear difference between GSI and GSM in effects on functional consequences, providing new insights into strategies for developing these drugs against Alzheimer's disease.

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A novel pathway for amyloid precursor protein processing

Cited by 147 publications

References 29 publications

γ-Secretase-dependent amyloid-β is increased in Niemann-Pick type C

γ-Secretase-dependent amyloid-β is increased in Niemann-Pick type C

Characterization of Intermediate Steps in Amyloid Beta (Aβ) Production under Near-native Conditions

Differential Effects between γ-Secretase Inhibitors and Modulators on Cognitive Function in Amyloid Precursor Protein-Transgenic and Nontransgenic Mice

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