Modulation of Lipid Kinase PI4KIIα Activity and Lipid Raft Association of Presenilin 1 Underlies γ-Secretase Inhibition by Ginsenoside (20S)-Rg3

Amyloid β-peptide (Aβ) pathology is an invariant feature of Alzheimer disease, preceding any detectable clinical symptoms by more than a decade. To this end, we seek to identify agents that can reduce Aβ levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced Aβ levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20S)-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the γ-secretase complex are enriched. The Aβ-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase IIα (PI4KIIα), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KIIα overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KIIα abolished the Aβ-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KIIα and phosphoinositide modulation in γ-secretase activity and Aβ biogenesis.

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The proteins BACE1 and BACE2 and β-secretase activity in normal and Alzheimer's disease brain

Biochemical Society Transactions ◽

10.1042/bst0350574 ◽

2007 ◽

Vol 35 (3) ◽

pp. 574-576 ◽

Cited By ~ 32

Author(s):

J.H. Stockley ◽

C. O'Neill

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Protein Levels ◽

Rate Limiting Step ◽

Secretase Activity ◽

Aβ Amyloid ◽

Ad Alzheimer’S Disease ◽

And Function

The insidious progression of AD (Alzheimer's disease) is believed to be linked closely to the production, accumulation and aggregation of the ∼4.5 kDa protein fragment called Aβ (amyloid β-peptide). Aβ is produced by sequential cleavage of the amyloid precursor protein by two enzymes referred to as β- and γ-secretase. β-Secretase is of central importance, as it catalyses the rate-limiting step in the production of Aβ and was identified 7 years ago as BACE1 (β-site APP-cleaving enzyme 1). Soon afterwards, its homologue BACE2 was discovered, and both proteins represent a new subclass of the aspartyl protease family. Studies examining the regulation and function of β-secretase in the normal and AD brain are central to the understanding of excessive production of Aβ in AD, and in targeting and normalizing this β-secretase process if it has gone awry in the disease. Several reports indicate this, showing increased β-secretase activity in AD, with recent findings by our group showing changes in β-secretase enzyme kinetics in AD brain caused by an increased Vmax. This article gives a brief review of studies which have examined BACE1 protein levels and β-secretase activity in control and AD brain, considering further the expression of BACE2 in the human brain.

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The Extreme C Terminus of Presenilin 1 Is Essential for γ-Secretase Complex Assembly and Activity

Journal of Biological Chemistry ◽

10.1074/jbc.m407717200 ◽

2004 ◽

Vol 279 (44) ◽

pp. 45564-45572 ◽

Cited By ~ 35

Author(s):

Anna Bergman ◽

Hanna Laudon ◽

Bengt Winblad ◽

Johan Lundkvist ◽

Jan Näslund

Keyword(s):

Transmembrane Domain ◽

Amyloid Β ◽

Presenilin 1 ◽

Amyloid Β Peptide ◽

Terminal Part ◽

Complex Assembly ◽

Terminal Fragment ◽

C Terminus ◽

Secretase Activity ◽

Endoproteolytic Cleavage

The γ-secretase complex catalyzes the cleavage of the amyloid precursor protein in its transmembrane domain resulting in the formation of the amyloid β-peptide and the cytoplasmic APP intracellular domain. The active γ-secretase complex is composed of at least four subunits: presenilin (PS), nicastrin, Aph-1, and Pen-2, where the presence of all components is critically required for γ-cleavage to occur. The PS proteins are themselves subjected to endoproteolytic cleavage resulting in the generation of an N-terminal and a C-terminal fragment that remain stably associated as a heterodimer. Here we investigated the effects of modifications on the C terminus of PS1 on PS1 endoproteolysis, γ-secretase complex assembly, and activity in cells devoid of endogenous PS. We report that certain mutations and, in particular, deletions of the PS1 C terminus decrease γ-secretase activity, PS1 endoproteolysis, and γ-secretase complex formation. We demonstrate that the N- and C-terminal PS1 fragments can associate with each other in mutants having C-terminal truncations that cause loss of interaction with nicastrin and Aph-1. In addition, we show that the C-terminal fragment of PS1 alone can mediate interaction with nicastrin and Aph-1 in PS null cells expressing only the C-terminal fragment of PS1. Taken together, these data suggest that the PS1 N- and C-terminal fragment intermolecular interactions are independent of an association with nicastrin and Aph-1, and that nicastrin and Aph-1 interact with the C-terminal part of PS1 in the absence of an association with full-length PS1 or the N-terminal fragment.

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

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2009.10.035 ◽

2010 ◽

Vol 48 (1) ◽

pp. 136-144 ◽

Cited By ~ 122

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

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Alterations in presenilin 1 processing by amyloid-β peptide in the rat retina

Experimental Brain Research ◽

10.1007/s00221-007-0904-5 ◽

2007 ◽

Vol 181 (1) ◽

pp. 69-77 ◽

Cited By ~ 2

Author(s):

Helena R. Watts ◽

Valerie Vince ◽

Desmond T. Walsh ◽

Laura G. Bresciani ◽

Stephen M. Gentleman ◽

...

Keyword(s):

Amyloid Β ◽

Presenilin 1 ◽

Amyloid Β Peptide ◽

Rat Retina

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Amyloid β-Peptide(1-42) Contributes to the Oxidative Stress and Neurodegeneration Found in Alzheimer Disease Brain

Brain Pathology ◽

10.1111/j.1750-3639.2004.tb00087.x ◽

2006 ◽

Vol 14 (4) ◽

pp. 426-432 ◽

Cited By ~ 149

Author(s):

D. Allan Butterfield ◽

Debra Boyd-Kimball

Keyword(s):

Oxidative Stress ◽

Alzheimer Disease ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Alzheimer Disease Brain

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Current and Future Treatments in Alzheimer Disease: An Update

Journal of Central Nervous System Disease ◽

10.1177/1179573520907397 ◽

2020 ◽

Vol 12 ◽

pp. 117957352090739 ◽

Cited By ~ 18

Author(s):

Konstantina G Yiannopoulou ◽

Sokratis G Papageorgiou

Keyword(s):

Alzheimer Disease ◽

Clinical Symptoms ◽

Neurofibrillary Tangle ◽

Treatment Strategies ◽

Specific Treatment ◽

Amyloid Β ◽

Cell Therapies ◽

Novel Biomarkers ◽

Disease Modifying ◽

Underlying Mechanisms

Disease-modifying treatment strategies for Alzheimer disease (AD) are still under extensive research. Nowadays, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance: 3 cholinesterase inhibitors and memantine. To block the progression of the disease, therapeutic agents are supposed to interfere with the pathogenic steps responsible for the clinical symptoms, classically including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation. Other underlying mechanisms are targeted by neuroprotective, anti-inflammatory, growth factor promotive, metabolic efficacious agents and stem cell therapies. Recent therapies have integrated multiple new features such as novel biomarkers, new neuropsychological outcomes, enrollment of earlier populations in the course of the disease, and innovative trial designs. In the near future different specific agents for every patient might be used in a “precision medicine” context, where aberrant biomarkers accompanied with a particular pattern of neuropsychological and neuroimaging findings could determine a specific treatment regimen within a customized therapeutic framework. In this review, we discuss potential disease-modifying therapies that are currently being studied and potential individualized therapeutic frameworks that can be proved beneficial for patients with AD.

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Topographic Distribution of Amyloid-β, Tau, and Atrophy in Patients With Behavioral/Dysexecutive Alzheimer Disease

Neurology ◽

10.1212/wnl.0000000000011081 ◽

2020 ◽

Vol 96 (1) ◽

pp. e81-e92

Author(s):

Joseph Therriault ◽

Tharick A. Pascoal ◽

Melissa Savard ◽

Andrea L. Benedet ◽

Mira Chamoun ◽

...

Keyword(s):

Alzheimer Disease ◽

Clinical Symptoms ◽

Characteristic Curve ◽

Tertiary Care ◽

Amyloid Β ◽

Executive Dysfunction ◽

Anterior Cingulate ◽

Amyloid Pet ◽

Clinical Criteria ◽

Tau Pet

ObjectiveTo determine the associations between amyloid-PET, tau-PET, and atrophy with the behavioral/dysexecutive presentation of Alzheimer disease (AD), how these differ from amnestic AD, and how they correlate to clinical symptoms.MethodsWe assessed 15 patients with behavioral/dysexecutive AD recruited from a tertiary care memory clinic, all of whom had biologically defined AD. They were compared with 25 patients with disease severity– and age-matched amnestic AD and a group of 131 cognitively unimpaired (CU) elderly individuals. All participants were evaluated with amyloid-PET with [18F]AZD4694, tau-PET with [18F]MK6240, MRI, and neuropsychological testing.ResultsVoxelwise contrasts identified patterns of frontal cortical tau aggregation in behavioral/dysexecutive AD, with peaks in medial prefrontal, anterior cingulate, and frontal insular cortices in contrast to amnestic AD. No differences were observed in the distribution of amyloid-PET or atrophy as determined by voxel-based morphometry. Voxelwise area under the receiver operating characteristic curve analyses revealed that tau-PET uptake in the medial prefrontal, anterior cingulate, and frontal insular cortices were best able to differentiate between behavioral/dysexecutive and amnestic AD (area under the curve 0.87). Voxelwise regressions demonstrated relationships between frontal cortical tau load and degree of executive dysfunction.ConclusionsOur results provide evidence of frontal cortical involvement of tau pathology in behavioral/dysexecutive AD and highlight the need for consensus clinical criteria in this syndrome.

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

Journal of Biological Chemistry ◽

10.1074/jbc.m111.246074 ◽

2012 ◽

Vol 287 (15) ◽

pp. 11991-12005 ◽

Cited By ~ 36

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.

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