scholarly journals Proton myo-inositol cotransporter is a novel γ-secretase associated protein that regulates Aβ production without affecting Notch cleavage

FEBS Journal ◽  
2015 ◽  
Vol 282 (17) ◽  
pp. 3438-3451 ◽  
Author(s):  
Yasuhiro Teranishi ◽  
Mitsuhiro Inoue ◽  
Natsuko Goto Yamamoto ◽  
Takahiro Kihara ◽  
Birgitta Wiehager ◽  
...  
Keyword(s):  
Notch Cleavage ◽  
Aβ Production

New Non-Peptidic Inhibitors of γ-Secretase Abolish Aβ Production Without Modifying Notch Cleavage

2002 ◽  
pp. 63-70
Author(s):  
A. Petit ◽  
F. Bihel ◽  
C. Alves da Costa ◽  
O. Pourquié ◽  
Y.-H. Suh ◽  
...  
Keyword(s):  
Notch Cleavage ◽  
Peptidic Inhibitors ◽  
Aβ Production

Selective Secretase Targeting for Alzheimer’s Disease Therapy

2021 ◽  
pp. 1-17
Author(s):  
Alvaro Miranda ◽  
Enrique Montiel ◽  
Henning Ulrich ◽  
Cristian Paz
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Neuroprotective Activity ◽  
Amyloid Β Protein ◽  
Secretase Activity ◽  
Membrane Bound ◽  
Aβ Production ◽  
Bace 1

Alzheimer’s disease (AD) is associated with marked atrophy of the cerebral cortex and accumulation of amyloid plaques and neurofibrillary tangles. Amyloid plaques are formed by oligomers of amyloid-β (Aβ) in the brain, with a length of 42 and 40 amino acids. α-secretase cleaves amyloid-β protein precursor (AβPP) producing the membrane-bound fragment CTFα and the soluble fragment sAβPPα with neuroprotective activity; β-secretase produces membrane-bound fragment CTFβ and a soluble fragment sAβPPβ. After α-secretase cleavage of AβPP, γ-secretase cleaves CTFα to produce the cytoplasmic fragment AICD and P3 in the non-amyloidogenic pathway. CTFβ is cleaved by γ-secretase producing AICD as well as Aβ in amyloidogenic pathways. In the last years, the study of natural products and synthetic compounds, such as α-secretase activity enhancers, β-secretase inhibitors (BACE-1), and γ-secretase activity modulators, have been the focus of pharmaceuticals and researchers. Drugs were improved regarding solubility, blood-brain barrier penetration, selectivity, and potency decreasing Aβ42. In this regard, BACE-1 inhibitors, such as Atabecestat, NB-360, Umibecestat, PF-06751979, Verubecestat, LY2886721, Lanabecestat, LY2811376, and Elenbecestat, were submitted to phase I-III clinical trials. However, inhibition of Aβ production did not recover cognitive functions or reverse the disease. Novel strategies are being developed, aiming at a partial reduction of Aβ production, such as the development of γ-secretase modulators or α-secretase enhancers. Such therapeutic tools shall focus on slowing down or minimizing the progression of neuronal damage. Here, we summarize structures and the activities of the latest compounds designed for AD treatment, with remarkable in vitro, in vivo, and clinical phase activities.

Extracellular Release of ILEI/FAM3C and Amyloid-β Is Associated with the Activation of Distinct Synapse Subpopulations

2021 ◽  
pp. 1-16
Author(s):  
Masaki Nakano ◽  
Yachiyo Mitsuishi ◽  
Lei Liu ◽  
Naoki Watanabe ◽  
Emi Hibino ◽  
...  
Keyword(s):  
Neuronal Activity ◽  
Epithelial Mesenchymal Transition ◽  
Surrogate Marker ◽  
Amyloid Β ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Extracellular Release ◽  
Activity Dependent ◽  
Aβ Production

Background: Brain amyloid-β (Aβ) peptide is released into the interstitial fluid (ISF) in a neuronal activity-dependent manner, and Aβ deposition in Alzheimer’s disease (AD) is linked to baseline neuronal activity. Although the intrinsic mechanism for Aβ generation remains to be elucidated, interleukin-like epithelial-mesenchymal transition inducer (ILEI) is a candidate for an endogenous Aβ suppressor. Objective: This study aimed to access the mechanism underlying ILEI secretion and its effect on Aβ production in the brain. Methods: ILEI and Aβ levels in the cerebral cortex were monitored using a newly developed ILEI-specific ELISA and in vivo microdialysis in mutant human Aβ precursor protein-knockin mice. ILEI levels in autopsied brains and cerebrospinal fluid (CSF) were measured using ELISA. Results: Extracellular release of ILEI and Aβ was dependent on neuronal activation and specifically on tetanus toxin-sensitive exocytosis of synaptic vesicles. However, simultaneous monitoring of extracellular ILEI and Aβ revealed that a spontaneous fluctuation of ILEI levels appeared to inversely mirror that of Aβ levels. Selective activation and inhibition of synaptic receptors differentially altered these levels. The evoked activation of AMPA-type receptors resulted in opposing changes to ILEI and Aβ levels. Brain ILEI levels were selectively decreased in AD. CSF ILEI concentration correlated with that of Aβ and were reduced in AD and mild cognitive impairment. Conclusion: ILEI and Aβ are released from distinct subpopulations of synaptic terminals in an activity-dependent manner, and ILEI negatively regulates Aβ production in specific synapse types. CSF ILEI might represent a surrogate marker for the accumulation of brain Aβ.

scholarly journals Transcriptional Regulation of PEN-2, a Key Component of the γ-Secretase Complex, by CREB

2006 ◽  
Vol 26 (4) ◽  
pp. 1347-1354 ◽  
Author(s):  
Ruishan Wang ◽  
Yun-wu Zhang ◽  
Ping Sun ◽  
Runzhong Liu ◽  
Xian Zhang ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Transcriptional Activity ◽  
Start Codon ◽  
Gamma Secretase ◽  
Mobility Shift ◽  
Endoproteolytic Cleavage ◽  
Notch Cleavage ◽  
Translational Start

ABSTRACT Gamma-secretase, which is responsible for the intramembranous cleavage of Alzheimer's β-amyloid precursor protein (APP), the signaling receptor Notch, and many other substrates, is a multiprotein complex consisting of at least four components: presenilin (PS), nicastrin, APH-1, and PEN-2. Despite the fact that PEN-2 is known to mediate endoproteolytic cleavage of full-length PS and APH-1 and nicastrin are required for maintaining the stability of the complex, the detailed physiological function of each component remain elusive. Unlike that of PS, the transcriptional regulation of PEN-2, APH-1, and nicastrin has not been investigated. Here, we characterized the upstream regions of the human PEN-2 gene and identified a 238-bp fragment located 353 bp upstream of the translational start codon as the key region necessary for the promoter activity. Further analysis revealed a CREB binding site located in the 238-bp region that is essential for the transcriptional activity of the PEN-2 promoter. Mutation of the CREB site abolished the transcriptional activity of the PEN-2 promoter. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed the binding of CREB to the PEN-2 promoter region both in vitro and in vivo. Activation of the CREB transcriptional factor by forskolin dramatically promoted the expression of PEN-2 mRNA and protein, whereas the other components of the γ-secretase complex remained unaffected. Forskolin treatment slightly increases the secretion of soluble APPα and Aβ without affecting Notch cleavage. These results demonstrate that expression of PEN-2 is regulated by CREB and suggest that the specific control of PEN-2 expression may imply additional physiological functions uniquely assigned to PEN-2.

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 Notch Cleavage: Nicastrin Helps Presenilin Make the Final Cut

2002 ◽  
Vol 12 (6) ◽  
pp. R200-R202 ◽  
Author(s):  
Eric C Lai
Keyword(s):  
Notch Cleavage

scholarly journals Interleukin-1β up-regulates TACE to enhance α-cleavage of APP in neurons: resulting decrease in Aβ production

2008 ◽  
Vol 104 (5) ◽  
pp. 1387-1393 ◽  
Author(s):  
Yuriko Tachida ◽  
Kazuhiro Nakagawa ◽  
Takashi Saito ◽  
Takaomi C. Saido ◽  
Takashi Honda ◽  
...  
Keyword(s):  
Interleukin 1Β ◽  
Aβ Production

scholarly journals Gleevec inhibits  -amyloid production but not Notch cleavage

2003 ◽  
Vol 100 (21) ◽  
pp. 12444-12449 ◽  
Author(s):  
W. J. Netzer ◽  
F. Dou ◽  
D. Cai ◽  
D. Veach ◽  
S. Jean ◽  
...  
Keyword(s):  
Notch Cleavage

Blockage of IL-17 Ameliorates Aβ-Induced Neurotoxicity and Cognitive Decline

2021 ◽  
Author(s):  
Yulan Liu ◽  
Yang Meng ◽  
Chenliang Zhou ◽  
Wenfang Xia ◽  
Lu Wang ◽  
...  
Keyword(s):  
Cognitive Decline ◽  
Lateral Ventricle ◽  
Hippocampal Neurons ◽  
Cognitive Impairments ◽  
Critical Role ◽  
Synaptic Dysfunction ◽  
Neural Damage ◽  
Primary Hippocampal Neurons ◽  
The Impact ◽  
Aβ Production

Abstract BackgroundNeuroinflammation plays a critical role in the pathophysiology of Alzheimer’s disease (AD), particularly in amyloid-β (Aβ) production. But the impact of the cytokine, interleukin-17A (IL-17) on the course of AD has not been well defined. The goal was to determine the effect of IL-17 on neural damage and whether IL-17 inhibitor (Y-320) could ameliorate Aβ-induced neurotoxicity and cognitive decline.MethodsThe expression level of IL-17 was analyzed in APP/PS1 mice. Then IL-17 was injected into the lateral ventricle of C57BL WT mice and roles on synaptic dysfunction and cognitive impairments were examined. Aβ42 was injected into the lateral ventricle of to mimic Aβ42 model mice. The effects of IL-17 inhibitor by oral gavage on Aβ42-induced neurotoxicity and cognitive decline were examined. ResultsWe found that IL-17 was increased in the hippocampus of APP/PS1 transgenic mouse, which has a fundamental role in mediating brain damage in neuroinflammatory processes. Furthermore, we reported that IL-17 was administrated in primary hippocampal neurons, leading to neural damage and synaptic dysfunction. At the same time, IL-17 caused synaptic dysfunction and cognitive impairments accompanying with increased of Aβ levels in mice. In addition, we found that Y-320 could rescue Aβ42–induced neural damage in primary hippocampal neurons, and ameliorate neuronal damage and cognitive impairments in Aβ42 model mice. Interestingly, we observed that IL-17 upregulated the production of soluble amyloid precursor protein β (sAPPβ) and phosphorylation of APP at T668 (pT668), moreover, Y-320 inhibited the Aβ production by down-regulation the sAPPβ and pT668. Conclusions Blockage of IL-17 might ameliorate Aβ-induced neurotoxicity and cognitive decline. These results strongly demonstrate a potential therapeutic role for IL-17 inhibitor in AD.

scholarly journals Implication of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

2021 ◽  
Author(s):  
Qi Wu ◽  
Leonardo Cortez ◽  
Razieh Kamali-Jamil ◽  
Valerie Sim ◽  
Holger Wille ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Influence Function ◽  
Critical Role ◽  
Amyloid Β ◽  
Cholesterol Accumulation ◽  
Aβ Peptides ◽  
Neuronal Viability ◽  
Cultured Astrocytes ◽  
Aβ Production

Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play a critical role in the development of Alzheimer's disease (AD) pathology. Aβ-containing neuronal exosomes, which represent a novel form of intercellular communication, have been shown to influence function/vulnerability of neurons in AD. Unlike neurons, the significance of exosomes derived from astrocytes remains unclear. In this study, we evaluated the significance of exosomes derived from U18666A-induced cholesterol-accumulated astrocytes in the development of AD pathology. Our results show that cholesterol accumulation decreases exosome secretion, whereas lowering cholesterol level increases exosome secretion from cultured astrocytes. Interestingly, exosomes secreted from U18666A-treated astrocytes contain higher levels of APP, APP-CTFs, soluble APP, APP secretases and Aβ1-40 than exosomes secreted from control astrocytes. Furthermore, we show that exosomes derived from U18666A-treated astrocytes can lead to neurodegeneration, which is attenuated by decreasing Aβ production or by neutralizing exosomal Aβ peptide with an Aβ antibody. These results, taken together, suggest that exosomes derived from cholesterol-accumulated astrocytes can play an important role in trafficking APP/Aβ peptides and influencing neuronal viability in the affected regions of the AD brain.

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