scholarly journals Identification of Novel γ-Secretase-associated Proteins in Detergent-resistant Membranes from Brain

2012 ◽  
Vol 287 (15) ◽  
pp. 11991-12005 ◽  
Author(s):  
Ji-Yeun Hur ◽  
Yasuhiro Teranishi ◽  
Takahiro Kihara ◽  
Natsuko Goto Yamamoto ◽  
Mitsuhiro Inoue ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Affinity Purification ◽  
Amyloid Β ◽  
Anion Channel ◽  
Amyloid Β Peptide ◽  
Voltage Dependent Anion Channel ◽  
App Processing ◽  
Associated Proteins ◽  
Detergent Resistant Membranes ◽  
Aβ Production

In Alzheimer disease, oligomeric amyloid β-peptide (Aβ) species lead to synapse loss and neuronal death. γ-Secretase, the transmembrane protease complex that mediates the final catalytic step that liberates Aβ from its precursor protein (APP), has a multitude of substrates, and therapeutics aimed at reducing Aβ production should ideally be specific for APP cleavage. It has been shown that APP can be processed in lipid rafts, and γ-secretase-associated proteins can affect Aβ production. Here, we use a biotinylated inhibitor for affinity purification of γ-secretase and associated proteins and mass spectrometry for identification of the purified proteins, and we identify novel γ-secretase-associated proteins in detergent-resistant membranes from brain. Furthermore, we show by small interfering RNA-mediated knockdown of gene expression that a subset of the γ-secretase-associated proteins, in particular voltage-dependent anion channel 1 (VDAC1) and contactin-associated protein 1 (CNTNAP1), reduced Aβ production (Aβ40 and Aβ42) by around 70%, whereas knockdown of presenilin 1, one of the essential γ-secretase complex components, reduced Aβ production by 50%. Importantly, these proteins had a less pronounced effect on Notch processing. We conclude that VDAC1 and CNTNAP1 associate with γ-secretase in detergent-resistant membranes and affect APP processing and suggest that molecules that interfere with this interaction could be of therapeutic use for Alzheimer disease.

scholarly journals Dieckol Ameliorates Aβ Production via PI3K/Akt/GSK-3β Regulated APP Processing in SweAPP N2a Cell

Marine Drugs ◽  
2021 ◽  
Vol 19 (3) ◽  
pp. 152
Author(s):  
Jeong-Hyun Yoon ◽  
Nayoung Lee ◽  
Kumju Youn ◽  
Mi Ra Jo ◽  
Hyeung-Rak Kim ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Inhibitory Effect ◽  
Proteolytic Processing ◽  
Amyloid Β Peptide ◽  
Phosphatidylinositol 3 Kinase ◽  
App Processing ◽  
Pi3k Inhibitor Ly294002 ◽  
Processing Enzymes ◽  
Gsk 3Β ◽  
Aβ Production

The proteolytic processing of amyloid precursor protein (APP) by β-secretase (BACE1) and γ-secretase releases amyloid-β peptide (Aβ), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer’s disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, dieckol exhibited the highest inhibitory effect on both intra- and extracellular Aβ accumulation. In addition, dieckol regulated the APP processing enzymes, such as α-secretase (ADAM10), β-secretase, and γ-secretase, presenilin-1 (PS1), and their proteolytic products, sAPPα and sAPPβ, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3β at Ser9, suggesting dieckol induced the activation of Akt, which phosphorylated GSK-3β. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3β activation and Aβ expression. In addition, co-treatment with LY294002 noticeably blocked the effect of dieckol on Aβ production, demonstrating that dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3β, resulting in the reduction in Aβ levels.

scholarly journals The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy

2015 ◽  
Vol 290 (52) ◽  
pp. 30670-30683 ◽  
Author(s):  
Angela Smilansky ◽  
Liron Dangoor ◽  
Itay Nakdimon ◽  
Danya Ben-Hail ◽  
Dario Mizrachi ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Β ◽  
Anion Channel ◽  
Voltage Dependent Anion Channel ◽  
Potential Target ◽  
Disease Therapy ◽  
Voltage Dependent

GULP1 is a novel APP-interacting protein that alters APP processing

2011 ◽  
Vol 436 (3) ◽  
pp. 631-639 ◽  
Author(s):  
Candy Yan Hao ◽  
Michael S. Perkinton ◽  
William Wai-Lun Chan ◽  
Ho Yin Edwin Chan ◽  
Christopher C. J. Miller ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Adaptor Protein ◽  
Amyloid Β Peptide ◽  
Interacting Proteins ◽  
Interacting Protein ◽  
App Processing ◽  
Aβ Amyloid ◽  
Full Complement ◽  
Ad Alzheimer’S Disease ◽  
Aβ Production

Altered production of Aβ (amyloid-β peptide), derived from the proteolytic cleavage of APP (amyloid precursor protein), is believed to be central to the pathogenesis of AD (Alzheimer's disease). Accumulating evidence reveals that APPc (APP C-terminal domain)-interacting proteins can influence APP processing. There is also evidence to suggest that APPc-interacting proteins work co-operatively and competitively to maintain normal APP functions and processing. Hence, identification of the full complement of APPc-interacting proteins is an important step for improving our understanding of APP processing. Using the yeast two-hybrid system, in the present study we identified GULP1 (engulfment adaptor protein 1) as a novel APPc-interacting protein. We found that the GULP1–APP interaction is mediated by the NPTY motif of APP and the GULP1 PTB (phosphotyrosine-binding) domain. Confocal microscopy revealed that a proportion of APP and GULP1 co-localized in neurons. In an APP–GAL4 reporter assay, we demonstrated that GULP1 altered the processing of APP. Moreover, overexpression of GULP1 enhanced the generation of APP CTFs (C-terminal fragments) and Aβ, whereas knockdown of GULP1 suppressed APP CTFs and Aβ production. The results of the present study reveal that GULP1 is a novel APP/APPc-interacting protein that influences APP processing and Aβ production.

scholarly journals GGA1-mediated endocytic traffic of LR11/SorLA alters APP intracellular distribution and amyloid-β production

2012 ◽  
Vol 23 (14) ◽  
pp. 2645-2657 ◽  
Author(s):  
Jeremy H. Herskowitz ◽  
Katrin Offe ◽  
Aniruddha Deshpande ◽  
Richard A. Kahn ◽  
Allan I. Levey ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Density Lipoprotein ◽  
Proteolytic Processing ◽  
Binding Motif ◽  
Amyloid Β Peptide ◽  
App Processing ◽  
Sirna Knockdown ◽  
Endocytic Traffic ◽  
Aβ Production ◽  
Mediated Reduction

Proteolytic processing of the amyloid-β precursor protein (APP) and generation of amyloid-β peptide (Aβ) are key events in Alzheimer's disease (AD) pathogenesis. Cell biological and genetic evidence has implicated the low-density lipoprotein and sorting receptor LR11/SorLA in AD through mechanisms related to APP and Aβ production. Defining the cellular pathway(s) by which LR11 modulates Aβ production is critical to understanding how changes in LR11 expression affect the development of Aβ pathology in AD progression. We report that the LR11 ectodomain is required for LR11-mediated reduction of Aβ and that mutagenesis of the LR11 Golgi-localizing, γ-adaptin ear homology domain, ADP-ribosylation factor (GGA)-binding motif affects the endosomal distribution of LR11, as well as LR11's effects on APP traffic and Aβ production. Targeted small interfering RNA (siRNA) knockdown studies of GGA1, GGA2, and GGA3 indicate a surprising degree of specificity toward GGA1, suggesting that GGA1 is a candidate regulator of LR11 traffic. Additional siRNA knockdown experiments reveal that GGA1 is necessary for both LR11 and β-site APP-cleaving enzyme-1 (BACE1) modulation of APP processing to Aβ. Mutagenesis of BACE1 serine 498 to alanine enhances BACE1 targeting to LR11-positive compartments and nullifies LR11-mediated reduction of Aβ. On basis of these results, we propose that GGA1 facilitates LR11 endocytic traffic and that LR11 modulates Aβ levels by promoting APP traffic to the endocytic recycling compartment.

scholarly journals The acute phase protein lactoferrin is a key feature of Alzheimer’s disease and predictor of Aβ burden through induction of APP amyloidogenic processing

2021 ◽  
Author(s):  
Andrew Tsatsanis ◽  
Andrew N. McCorkindale ◽  
Bruce X. Wong ◽  
Ellis Patrick ◽  
Tim M. Ryan ◽  
...  
Keyword(s):  
Acute Phase ◽  
Acute Phase Protein ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
App Processing ◽  
Amyloidogenic Processing ◽  
Phase Protein ◽  
Learning Analysis ◽  
Aβ Production

AbstractAmyloidogenic processing of the amyloid precursor protein (APP) forms the amyloid-β peptide (Aβ) component of pathognomonic extracellular plaques of AD. Additional early cortical changes in AD include neuroinflammation and elevated iron levels. Activation of the innate immune system in the brain is a neuroprotective response to infection; however, persistent neuroinflammation is linked to AD neuropathology by uncertain mechanisms. Non-parametric machine learning analysis on transcriptomic data from a large neuropathologically characterised patient cohort revealed the acute phase protein lactoferrin (Lf) as the key predictor of amyloid pathology. In vitro studies showed that an interaction between APP and the iron-bound form of Lf secreted from activated microglia diverted neuronal APP endocytosis from the canonical clathrin-dependent pathway to one requiring ADP ribosylation factor 6 trafficking. By rerouting APP recycling to the Rab11-positive compartment for amyloidogenic processing, Lf dramatically increased neuronal Aβ production. Lf emerges as a novel pharmacological target for AD that not only modulates APP processing but provides a link between Aβ production, neuroinflammation and iron dysregulation.

Cholesterol and Alzheimer's disease

2002 ◽  
Vol 30 (4) ◽  
pp. 525-529 ◽  
Author(s):  
B. Wolozin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Hmg Coa Reductase ◽  
Production Studies ◽  
Amino Acid Peptide ◽  
Reductase Inhibitors ◽  
Coa Reductase ◽  
Aβ Production

Accumulation of a 40–42-amino acid peptide, termed amyloid-β peptide (Aβ), is associated with Alzheimer's disease (AD), and identifying medicines that inhibit Aβ could help patients with AD. Recent evidence suggests that a class of medicines that lower cholesterol by blocking the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), termed statins, can inhibit Aβ production. Increasing evidence suggests that the enzymes that generate Aβ function best in a high-cholesterol environment, which might explain why reducing cholesterol would inhibit Aβ production. Studies using both neurons and peripheral cells show that reducing cellular cholesterol levels, by stripping off the cholesterol with methyl-β-cyclodextrin or by treating the cells with HMG-CoA reductase inhibitors, decreases Aβ production. Studies performed on animal models and on humans concur with these results. In humans, lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce Aβ levels in blood of patients by up to 40%. The putative role of Aβ in AD raises the possibility that treating patients with statins might lower Aβ, and thereby either delay the occurrence of AD or retard the progression of AD. Two large retrospective studies support this hypothesis. Both studies suggest that patients taking statins had an approx. 70% lower risk of developing AD. Since statins are widely used by doctors, their ability to reduce Aβ offers a putative therapeutic strategy for treating AD by using medicines that have already been proved safe to use in humans.

scholarly journals In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid β-peptide of APP

2010 ◽  
Vol 48 (1) ◽  
pp. 136-144 ◽  
Author(s):  
D. Allan Butterfield ◽  
Veronica Galvan ◽  
Miranda Bader Lange ◽  
Huidong Tang ◽  
Renã A. Sowell ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer Disease ◽  
Transgenic Mice ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Methionine 35

scholarly journals Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes

2018 ◽  
Vol 215 (6) ◽  
pp. 1665-1677 ◽  
Author(s):  
Ying Du ◽  
Yingjun Zhao ◽  
Chuan Li ◽  
Qiuyang Zheng ◽  
Jing Tian ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Β ◽  
Neuritic Plaque ◽  
App Processing ◽  
Disease Phenotypes ◽  
Kinase C ◽  
Bace1 Expression ◽  
Pkc Isoforms ◽  
Exon 9 ◽  
Aβ Generation

β-amyloid protein (Aβ) plays a central role in the pathogenesis of Alzheimer disease (AD). Aβ is generated from sequential cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. Although activation of some protein kinase C (PKC) isoforms such as PKCα and ε has been shown to regulate nonamyloidogenic pathways and Aβ degradation, it is unclear whether other PKC isoforms are involved in APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain. PKCδ knockdown reduces BACE1 expression, BACE1-mediated APP processing, and Aβ production. Conversely, overexpression of PKCδ increases BACE1 expression and Aβ generation. Importantly, inhibition of PKCδ by rottlerin markedly reduces BACE1 expression, Aβ levels, and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin-1 with an exon 9 deletion–transgenic AD mouse model. Our study indicates that PKCδ plays an important role in aggravating AD pathogenesis, and PKCδ may be a potential target in AD therapeutics.

scholarly journals Intracellular APP Processing and Aβ Production in Alzheimer Disease

1999 ◽  
Vol 58 (8) ◽  
pp. 787-794 ◽  
Author(s):  
Christina A. Wilson ◽  
Robert W. Doms ◽  
Virginia M-Y Lee
Keyword(s):  
Alzheimer Disease ◽  
App Processing ◽  
Aβ Production
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