アルツハイマー病標的/APP αセクレターゼ α切断の低下を防ぐ16の方法

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APP アルファ-セクレターゼを増加させる

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概要

αセクレターゼによるアミロイドβ区画の切断

αセクレターゼは、アミロイドβが作り出されるAPPを切断する切断酵素。

しかしAPPのアミロイドβとなる中央部分を切断するため、アミロイドβは切り出されず代わりにsAPPαが切り出され細胞外に放出される。

そのためαセクレターゼによるAPPα切断(プロセシング)は、アルツハイマー病の発症原因とされるアミロイドβの産生を妨害することができる。

「app alpha secretase」の画像検索結果

Alpha secretase - Wikipedia
切断されたsAPPαの神経保護特性

さらにsAPPαは、それ自体が神経保護特性を有すると推定されており、αセクレターゼ切断の促進はアミロイドβ産生の阻害と神経保護のダブルの作用でルツハイマー病に対抗しえる。

Increased Activity-Regulating and Neuroprotective Efficacy of Alpha-Secretase-Derived Secreted Amyloid Precursor Protein Conferred by a C-terminal Heparin-Binding Domain - PubMed
Proteolytic cleavage of beta-amyloid precursor protein (beta APP) by alpha-secretase results in release of one secreted form (sAPP) of APP (sAPP alpha), whereas...
p3ペプチドも無毒性

APPα切断後の残りのAPPをγセクレターゼが切断することで、無毒性のp3ペプチドが放出される。

「app alpha secretase p3」の画像検索結果

https://www.researchgate.net/figure/APP-processing-similarities-to-Notch-processing-Both-APP-and-Notch-receptor-may-undergo_fig1_225276421

 

ADAM10

ADAM9、ADAM10およびADAM17は、αセクレターゼ活性を有する酵素であることが示されている。

ADAMA10は間接的にαセクレターゼの活性に寄与する。

Activation of α-Secretase Cleavage - PubMed
Alpha-secretase-mediated cleavage of the amyloid precursor protein (APP) releases the neuroprotective APP fragment sαAPP and prevents amyloid β peptide (Aβ) gen...

 

ADAM10はα-セクレターゼ活性を有するタンパク質と同定されている。

ADAM10は、中枢神経系の発達およびニューロン/グリア分化を調節する。

ADAM10はシナプス形成および可塑性を調節するために多様なニューロン基質を使用する。

ADAM10はてんかん、プリオン、ハンチントン病、アルツハイマー病に関連しており、アルツハイマー病の魅力的な治療標的。

The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain
Proteins belonging to the ‘A Disintegrin And Metalloproteinase’ (ADAM) family are membrane-anchored proteases that are able to cleave the extracellula…

 

The alpha secretase ADAM10: A metalloprotease with multiple functions in the brain
Proteins belonging to the ‘A Disintegrin And Metalloproteinase’ (ADAM) family are membrane-anchored proteases that are able to cleave the extracellula…

ADAM10増加因子

ビタミンA(レチノイン酸)

Up-regulation of the Alpha-Secretase ADAM10 by Retinoic Acid Receptors and Acitretin - PubMed
Late-onset Alzheimer's disease is often connected with nutritional misbalance, such as enhanced cholesterol intake, deficiency in polyunsaturated fatty acids, o...

メラトニン

メラトニンはADAM転写アゴニストとして明確に作用し、αセクレターゼを刺激することでβセクレターゼとγセクレターゼの両方をダウンレギュレーションする。

Melatonin Stimulates the Nonamyloidogenic Processing of βAPP Through the Positive Transcriptional Regulation of ADAM10 and ADAM17 - PubMed
Melatonin controls many physiological functions including regulation of the circadian rhythm and clearance of free radicals and neuroprotection. Importantly, me...
Mechanisms of Melatonin in Alleviating Alzheimer's Disease - PubMed
Alzheimer's disease (AD) is a chronic, progressive and prevalent neurodegenerative disease characterized by the loss of higher cognitive functions and an associ...

メタロチオネイン3(MT3)

メタロチオネイン3(MT3)は亜鉛-銅ホメオスタシスにおいて重要な役割を果たすタンパク質。

成長阻害因子として知られており、主に中枢神経系のおいて発現される。

ヒトMT-3は、重金属の解毒、代謝の調節、および中枢神経系におけるフリーラジカルの酸化的損傷に対する保護に関与すると推定されており、重要な神経修飾物質および神経保護の役割を果たしえる。


アルツハイマー病患者の脳内ではMT3レベルの低下が観察されている。

Metallothionein-3 - Wikipedia

PC7およびフリンの発現を増加させることにより活性型ADAM10の生成に役割を果たす。

Metallothionein-III Increases ADAM10 Activity in Association With Furin, PC7, and PKCα During Non-Amyloidogenic Processing - PubMed
A-disintegrin and metalloproteinase 10 (ADAM10) is involved in the generation of amyloid-β (Aβ) during amyloid precursor protein (APP) processing, and has a pro...

 

ドネペジル

ドネペジルはAPP代謝を非アミロイド形成経路に強力にシフトさせることが示されている。

ドネペジルは血漿膜へのADAM10の輸送を促進し、インビトロでα-セクレターゼ活性を増強する。

他のアセチルコリンエステラーゼ阻害剤がADAM10活性の増加に作用するか否かはまだ検討されていない。

Acetylcholinesterase Inhibitors Increase ADAM10 Activity by Promoting Its Trafficking in Neuroblastoma Cell Lines - PubMed
Acetylcholinesterase inhibitors (AChEIs) are the only currently available drugs for treating Alzheimer's Disease (AD). Some authors have suggested a function of...

クルクミン

インビトロでADAM10発現およびsAPPα分泌を増強することが示された。

Activation of α-Secretase by Curcumin-Aminoacid Conjugates - PubMed
The extracellular senile plaques observed in Alzheimer's disease (AD) patients are mainly composed of amyloid peptides produced from the β-amyloid precursor pro...

ジンゲロール(生姜)

[6]-gingerol as a Cancer Chemopreventive Agent: A Review of Its Activity on Different Steps of the Metastatic Process | Request PDF
Request PDF | -gingerol as a Cancer Chemopreventive Agent: A Review of Its Activity on Different Steps of the Metastatic Process | For many years, ginger or gin...

レスベラトロール

高レベルのコレステロールはADAM10、BACE1の発現と局在化に変化をもたらす。レスベラトロールは、コレステロールの恒常性を回復し、Sirt1発現を増強することによりアミロイド形成の負荷を緩和させる。

Resveratrol Intervenes Cholesterol- And Isoprenoid-Mediated Amyloidogenic Processing of AβPP in Familial Alzheimer's Disease - PubMed
Deterioration of cholesterol metabolism has recently been a frontier subject of investigation in the field of Alzheimer's disease (AD). Though amyloid-β protein...

アセチル-L-カルニチン

アセチル-L-カルニチンは、αセクレターゼ活性を刺激を介してβセクレターゼ媒介経路を減少させることが示されている。

Modulatory Effect of acetyl-L-carnitine on Amyloid Precursor Protein Metabolism in Hippocampal Neurons - PubMed
Alzheimer Disease is the most common chronic neurodegenerative disorder associated with aging. Nevertheless, its pharmacological therapy is still an unresolved ...
Acetyl-L-carnitine-induced Up-Regulation of Heat Shock Proteins Protects Cortical Neurons Against Amyloid-Beta Peptide 1-42-mediated Oxidative Stress and Neurotoxicity: Implications for Alzheimer's Disease - PubMed
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition and by senile plaques and neurofibrillary tan...

スタチン

 

その他

SOX-2
PAX2

ADAM10阻害

高すぎるコレステロール
Resveratrol Intervenes Cholesterol- And Isoprenoid-Mediated Amyloidogenic Processing of AβPP in Familial Alzheimer's Disease - PubMed
Deterioration of cholesterol metabolism has recently been a frontier subject of investigation in the field of Alzheimer's disease (AD). Though amyloid-β protein...
低すぎるコレステロール
Statins and the Squalene Synthase Inhibitor Zaragozic Acid Stimulate the Non-Amyloidogenic Pathway of Amyloid-Beta Protein Precursor Processing by Suppression of Cholesterol Synthesis - PubMed
Cholesterol-lowering drugs such as statins influence the proteolytic processing of the amyloid-beta protein precursor (AbetaPP) and are reported to stimulate th...
Statins Cause Intracellular Accumulation of Amyloid Precursor Protein, Beta-Secretase-Cleaved Fragments, and Amyloid Beta-Peptide via an Isoprenoid-Dependent Mechanism - PubMed
The use of statins, 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that block the synthesis of mevalonate (and downstream products such as cholesterol and ...

αセクレターゼ活性因子

運動

運動によるBDNFはAPPのα セクレターゼ プロセシングを増強することによってアミロイドβ 産生低下させる。

Exercise and BDNF Reduce Aβ Production by Enhancing α-Secretase Processing of APP - PubMed
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by aggregation of toxic forms of amyloid β peptide (Aβ). Treatment strategie...

緑茶カテキン EGCG

PKC経路を介してα-セクレターゼを刺激し、ADマウスの脳アミロイド沈着を減少させることが示されている。

Neuroprotection and Neurorescue Against Abeta Toxicity and PKC-dependent Release of Nonamyloidogenic Soluble Precursor Protein by Green Tea Polyphenol (-)-epigallocatechin-3-gallate - PubMed
Green tea extract and its main polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) possess potent neuroprotective activity in cell culture and mice mod...
Green Tea (-)-epigallocatechin-3-gallate Inhibits Beta-Amyloid-Induced Cognitive Dysfunction Through Modification of Secretase Activity via Inhibition of ERK and NF-kappaB Pathways in Mice - PubMed
Alzheimer's disease (AD) is characterized by the extracellular deposition of beta-amyloid peptide (Abeta) in cerebral plaques. Abeta is derived from the beta-am...
ADAM10 Activation Is Required for Green Tea (-)-epigallocatechin-3-gallate-induced Alpha-Secretase Cleavage of Amyloid Precursor Protein - PubMed
Recently, we have shown that green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) exerts a beneficial role on reducing brain Abeta levels, resulting in mi...
Green Tea epigallocatechin-3-gallate (EGCG) Modulates Amyloid Precursor Protein Cleavage and Reduces Cerebral Amyloidosis in Alzheimer Transgenic Mice - PubMed
Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by deposition of beta-amyloid (Abeta) peptides as senile plaqu...

レスベラトロール

Dietary Supplementation With Resveratrol Reduces Plaque Pathology in a Transgenic Model of Alzheimer's Disease - PubMed
Resveratrol, a polyphenol found in red wine, peanuts, soy beans, and pomegranates, possesses a wide range of biological effects. Since resveratrol's properties ...
Moderate Consumption of Cabernet Sauvignon Attenuates Abeta Neuropathology in a Mouse Model of Alzheimer's Disease - PubMed
Recent studies suggest that moderate red wine consumption reduces the incidence of Alzheimer's disease (AD) clinical dementia. Using Tg2576 mice, which model AD...

ラクトフェリン

鼻腔内ラクトフェリン投与、ERK1 / 2-CREBおよびHIF-1α経路を介してADマウスのα-セクレターゼ依存性のAPPプロセシングを増強する。→アミロイドβ生成の低下。

Intranasal Lactoferrin Enhances α-Secretase-Dependent Amyloid Precursor Protein Processing via the ERK1/2-CREB and HIF-1α Pathways in an Alzheimer's Disease Mouse Model - PubMed
Growing evidence suggests that lactoferrin (Lf), an iron-binding glycoprotein, is a pleiotropic functional nutrient. In addition, Lf was recently implicated as ...

ジンセノサイドRe

ジンセノサイドReはPPARγ活性を介して、BACE1を阻害し、アミロイドβ産生を減少させる。in vivo

Ginsenoside Re Reduces Aβ Production by Activating PPARγ to Inhibit BACE1 in N2a/APP695 Cells - PubMed
Alzheimer's disease (AD) is a neurodegenerative disease characterized by β-amyloid protein (Aβ) deposition. Reducing the Aβ load may be a new perspective for AD...

クリプトタンノシン

Cryptotanshinione Upregulates Alpha-Secretase by Activation PI3K Pathway in Cortical Neurons - PubMed
The amyloid precursor protein (APP) is cleaved enzymatically by nonamyloidogenic and amyloidogenic pathways. alpha-Secretase cleaves APP within beta amyloid pro...
Tanshinone Congeners Improve Memory Impairments Induced by Scopolamine on Passive Avoidance Tasks in Mice - PubMed
Tanshinones are a group of diterpenoids found in the roots of Salvia miltiorrhiza Bunge which has been used to treat cardiac disease. In the present study, we i...

セレギリン

ランダム化比較試験 長期投与による有益な効果はセレギリンの神経保護またはニューロンの救済による作用機序であることを支持する。

Selegiline in the Treatment of Alzheimer's Disease: A Long-Term Randomized Placebo-Controlled Trial. Czech and Slovak Senile Dementia of Alzheimer Type Study Group - PubMed
Selegiline has a long-term beneficial effect in Alzheimer's disease on memory modalities that reflect the function of the prefrontal areas of the brain, which a...

デプレニルがPC12細胞において用量依存的にα-セクレターゼ活性を増加させることができることを示した。

Involvement of protein trafficking in deprenyl-induced α-secretase activity regulation in PC12 cells
Deprenyl is a selective B-type monoamine oxidase inhibitor and a neuroprotective agent that has been used to slow the progress of Alzheimer's disease …

アトルバスタチン

Association Between Statin Use and Alzheimer's Disease - PubMed
In this study, following adjustment for confounding factors, a statistically significant inverse association between statin use and AD was observed. The results...
Atorvastatin-induced Activation of Alzheimer's Alpha Secretase Is Resistant to Standard Inhibitors of Protein Phosphorylation-Regulated Ectodomain Shedding - PubMed
Studies of metabolism of the Alzheimer amyloid precursor protein (APP) have focused much recent attention on the biology of juxta- and intra-membranous protease...
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