Zinc Enhances Synthesis of Presenilin 1 in Mouse Primary Cortical Culture

Park, In-Ho; Jung, Min Whan; Mori, Hiroshi; Mook‐Jung, Inhee

doi:10.1006/bbrc.2001.5243

Cited by 22 publications

(8 citation statements)

References 40 publications

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“…Previous studies have demonstrated that the metabolism of PSEN1 and its fragments is dependent on cell type and condition [35][36][37][38]. Our study demonstrated that exposure to tunicamycin increased transcription of endogenous PSEN1 mRNA and accumulation of PSEN1 holoprotein in HEK293 cells, neuroblastoma cell lines (GOTO), and glioma cell lines (KNS-42).…”

Section: Discussionsupporting

confidence: 62%

Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress

Jin

Sanjo

Uchihara

et al. 2010

JAD

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Abstract. Presenilin-1 (PSEN1) is a primary component of the γ-secretase complex, and total levels of its holoprotein and endoproteolytic fragments are tightly regulated. We examined the effects of several types of endoplasmic reticulum (ER) stress on quantitative changes in the levels of PSEN1 mRNA, holoprotein, and fragments. The ER stress-inducing chemical compounds tunicamycin, brefeldin-A, thapsigargin, and staurosporine were added to the culture media of various human cell lines. Tunicamycin treatment caused a doubling of PSEN1 holoprotein production in HEK293 cells and an increase in holoprotein production to approximately 180% in GOTO human neuroblastoma and KNS-42 human glioma cell lines, without changing the amounts of PSEN1 N-or C-terminal fragments. The elevated holoprotein level in HEK293 cells was accompanied by an increase in PSEN1 mRNA expression. HEK293 cells that stably overexpressed PSEN1 holoprotein showed increased resistance to ER stress induced by tunicamycin, but they did not show resistance to ER stress caused by thapsigargin, a specific inhibitor of sarco ER calcium-ATPase (SERCA). In wild-type HEK293 cells under ER stress induced by tunicamycin, an increased amount of SERCA interacted with PSEN1 holoprotein. PSEN1 production varied among cell types and circumstances. The results suggested that the holoprotein forms a complex with the SERCA channel and participates in the regulation of intracellular calcium homeostasis. These findings provide support for the calcium hypothesis of Alzheimer's disease.

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Section: Discussionsupporting

confidence: 62%

Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress

Jin

Sanjo

Uchihara

et al. 2010

JAD

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“…Zinc may also interfere with APP processing and function as these processes are coordinated by secretases under the zinc regulation. This metal increases the synthesis of PS-1 (Park et al, 2001 ); however, the γ-secretase activity is inhibited by Zn 2+ (Hoke et al, 2007 ). Zinc binds directly to Aβ, hiding its proteolytic cleavage site (Bush et al, 1994b ) and therefore inhibiting its degradation by matrix metalloproteases (Crouch et al, 2009 ).…”

Section: Biometal Dyshomeostasismentioning

confidence: 99%

Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease

et al. 2016

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HIGHLIGHTS• ASS234 is a MTDL compound containing a moiety from Donepezil and the propargyl group from the PF 9601N, a potent and selective MAO B inhibitor. This compound is the most advanced anti-Alzheimer agent for preclinical studies identified in our laboratory.• Derived from ASS234 both multipotent donepezil-indolyl (MTDL-1) and donepezil-pyridyl hybrids (MTDL-2) were designed and evaluated as inhibitors of AChE/BuChE and both MAO isoforms. MTDL-2 showed more high affinity toward the four enzymes than MTDL-1.• MTDL-3 and MTDL-4, were designed containing the N-benzylpiperidinium moiety from Donepezil, a metal-chelating 8-hydroxyquinoline group and linked to a N-propargyl core and they were pharmacologically evaluated.• The presence of the cyano group in MTDL-3, enhanced binding to AChE, BuChE and MAO A. It showed antioxidant behavior and it was able to strongly complex Cu(II), Zn(II) and Fe(III).• MTDL-4 showed higher affinity toward AChE, BuChE.• MTDL-3 exhibited good brain penetration capacity (ADMET) and less toxicity than Donepezil. Memory deficits in scopolamine-lesioned animals were restored by MTDL-3.• MTDL-3 particularly emerged as a ligand showing remarkable potential benefits for its use in AD therapy.Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept ® ) but with limited therapeutic success. This might be due to the Unzeta et al.New MTDLs for Alzheimer's Disease complex multifactorial nature of AD, a fact that has prompted the design of new MultiTarget-Directed Ligands (MTDL) based on the "one molecule, multiple targets" paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory, and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N-benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) with special emphasis on compound ASS234, an N-propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy.

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“…Neonatal cortical cultures exposed to zinc increases C-terminal fragmentation of PS1 by enhancing synthesis of the protein (Park et al, 2001). However, zinc induces oligomerization of an APP γ-secretase substrate and inhibits its processing, which supports a role for zinc dysregulation in Aβ processing (Hoke et al, 2005; Greenough et al, 2011).…”

Section: Metal and Cholesterol Modulation Of App And Aβ Metabolismmentioning

confidence: 99%

Metals and cholesterol: two sides of the same coin in Alzheimerâ€™s disease pathology

Wong

Hung

Bush

et al. 2014

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease. It begins years prior to the onset of clinical symptoms, such as memory loss and cognitive decline. Pathological hallmarks of AD include the accumulation of β-amyloid in plaques and hyperphosphorylated tau in neurofibrillary tangles. Copper, iron, and zinc are abnormally accumulated and distributed in the aging brain. These metal ions can adversely contribute to the progression of AD. Dysregulation of cholesterol metabolism has also been implicated in the development of AD pathology. To date, large bodies of research have been carried out independently to elucidate the role of metals or cholesterol on AD pathology. Interestingly, metals and cholesterol affect parallel molecular and biochemical pathways involved in AD pathology. The possible links between metal dyshomeostasis and altered brain cholesterol metabolism in AD are reviewed.

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Zinc Enhances Synthesis of Presenilin 1 in Mouse Primary Cortical Culture

Cited by 22 publications

References 40 publications

Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress

Presenilin-1 Holoprotein is an Interacting Partner of Sarco Endoplasmic Reticulum Calcium-ATPase and Confers Resistance to Endoplasmic Reticulum Stress

Multi-Target Directed Donepezil-Like Ligands for Alzheimer's Disease

Metals and cholesterol: two sides of the same coin in Alzheimerâ€™s disease pathology

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