scholarly journals Assembly of γ-secretase occurs through stable dimers after exit from the endoplasmic reticulum

2021 ◽  
Vol 220 (9) ◽  
Author(s):  
Rosanne Wouters ◽  
Christine Michiels ◽  
Ragna Sannerud ◽  
Bertrand Kleizen ◽  
Katleen Dillen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Presenilin 1 ◽  
Physiological Processes ◽  
Spatiotemporal Regulation ◽  
Biochemical Assays ◽  
Copii Vesicles ◽  
Stepwise Assembly

γ-Secretase affects many physiological processes through targeting >100 substrates; malfunctioning links γ-secretase to cancer and Alzheimer’s disease. The spatiotemporal regulation of its stoichiometric assembly remains unresolved. Fractionation, biochemical assays, and imaging support prior formation of stable dimers in the ER, which, after ER exit, assemble into full complexes. In vitro ER budding shows that none of the subunits is required for the exit of others. However, knockout of any subunit leads to the accumulation of incomplete subcomplexes in COPII vesicles. Mutating a DPE motif in presenilin 1 (PSEN1) abrogates ER exit of PSEN1 and PEN-2 but not nicastrin. We explain this by the preferential sorting of PSEN1 and nicastrin through Sec24A and Sec24C/D, respectively, arguing against full assembly before ER exit. Thus, dimeric subcomplexes aided by Sec24 paralog selectivity support a stepwise assembly of γ-secretase, controlling final levels in post-Golgi compartments.

scholarly journals Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization

2017 ◽  
Vol 114 (48) ◽  
pp. 12731-12736 ◽  
Author(s):  
Rui Zhou ◽  
Guanghui Yang ◽  
Yigong Shi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protease Activity ◽  
Underlying Mechanism ◽  
Dominant Negative ◽  
Presenilin 1 ◽  
Dominant Negative Effect ◽  
Loss Of Function ◽  
Negative Effect

γ-secretase is an intramembrane protease complex consisting of nicastrin, presenilin-1/2, APH-1a/b, and Pen-2. Hydrolysis of the 99-residue transmembrane fragment of amyloid precursor protein (APP-C99) by γ-secretase produces β-amyloid (Aβ) peptides. Pathogenic mutations in PSEN1 and PSEN2, which encode the catalytic subunit presenilin-1/2 of γ-secretase, lead to familial Alzheimer’s disease in an autosomal dominant manner. However, the underlying mechanism of how the mutant PSEN gene may affect the function of the WT allele remains to be elucidated. Here we report that each of the loss-of-function γ-secretase variants that carries a PSEN1 mutation suppresses the protease activity of the WT γ-secretase on Aβ production. Each of these γ-secretase variants forms a stable oligomer with the WT γ-secretase in vitro in the presence of the detergent CHAPSO {3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy-1-propanesulfonate}, but not digitonin. Importantly, robust protease activity of γ-secretase is detectable in the presence of CHAPSO, but not digitonin. These experimental observations suggest a dominant negative effect of the γ-secretase, in which the protease activity of WT γ-secretase is suppressed by the loss-of-function γ-secretase variants through hetero-oligomerization. The relevance of this finding to the genesis of Alzheimer’s disease is critically evaluated.

scholarly journals Familial Alzheimer's Disease–Linked Presenilin 1 Variants Elevate Aβ1–42/1–40 Ratio In Vitro and In Vivo

Neuron ◽  
1996 ◽  
Vol 17 (5) ◽  
pp. 1005-1013 ◽  
Author(s):  
David R. Borchelt ◽  
Gopal Thinakaran ◽  
Christopher B. Eckman ◽  
Michael K. Lee ◽  
Frances Davenport ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Presenilin 1 ◽  
Familial Alzheimer’S Disease ◽  
Familial Alzheimer's Disease

Familial Alzheimer's disease presenilin 1 mutation M146V increases gamma secretase cutting of p75NTR in vitro

2007 ◽  
Vol 1147 ◽  
pp. 248-255 ◽  
Author(s):  
Caroline Sara Hatchett ◽  
Sue Tyler ◽  
Dawn Armstrong ◽  
David Dawbarn ◽  
Shelley Jane Allen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Presenilin 1 ◽  
Gamma Secretase ◽  
Familial Alzheimer’S Disease ◽  
Presenilin 1 Mutation ◽  
Familial Alzheimer's Disease

scholarly journals Therapeutic Effects of Natural Compounds and Small Molecule Inhibitors Targeting Endoplasmic Reticulum Stress in Alzheimer’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Xun Gao ◽  
Yuanyuan Xu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Natural Compounds ◽  
Therapeutic Effects

Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by progressive cognitive impairment and memory loss. So far, the pathogenesis of AD has not been fully understood. Research have shown that endoplasmic reticulum (ER) stress and unfolded protein response (UPR) participate in the occurrence and development of AD. Furthermore, various studies, both in vivo and in vitro, have shown that targeting ER stress and ER stress-mediated apoptosis contribute to the recovery of AD. Thus, targeting ER stress and ER stress-mediated apoptosis may be effective for treating AD. In this review, the molecular mechanism of ER stress and ER stress-mediated apoptosis, as well as the therapeutic effects of some natural compounds and small molecule inhibitors targeting ER stress and ER stress-mediated apoptosis in AD will be introduced.

Acetylcholinesterase Inhibitory Potential and Antioxidant Activities of Five Cultivars of Rosa Damascena Mill. From Isparta, Turkey

2020 ◽  
Vol 18 (4) ◽  
pp. 354-359
Author(s):  
Shirin Tarbiat ◽  
Azize Simay Türütoğlu ◽  
Merve Ekingen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radical ◽  
Neurodegenerative Disorder ◽  
Antioxidant Activities ◽  
Radical Scavenging ◽  
Acetylcholinesterase Activity ◽  
Rosa Damascena ◽  
Free Radical Damage

Alzheimer's disease is a neurodegenerative disorder characterized by memory loss and impairment of language. Alzheimer's disease is strongly associated with oxidative stress and impairment in the cholinergic pathway, which results in decreased levels of acetylcholine in certain areas of the brain. Hence, inhibition of acetylcholinesterase activity has been recognized as an acceptable treatment against Alzheimer's disease. Nature provides an array of bioactive compounds, which may protect against free radical damage and inhibit acetylcholinesterase activity. This study compares the in vitro antioxidant and anticholinesterase activities of hydroalcoholic extracts of five cultivars of Rosa Damascena Mill. petals (R. damascena 'Bulgarica', R. damascena 'Faik', R. damascena 'Iranica', R. damascena 'Complex-635' and R. damascena 'Complex-637') from Isparta, Turkey. The antioxidant activities of the hydroalcoholic extracts were tested for ferric ion reduction and DPPH radical scavenging activities. The anti-acetylcholinesterase activity was also evaluated. All rose cultivars showed a high potency for scavenging free radical and inhibiting acetylcholinesterase activity. There was a significant correlation between antioxidant and acetylcholinesterase inhibitory activity. Among cultivars, Complex-635 showed the highest inhibitory effect with an IC50 value of 3.92 µg/mL. Our results suggest that all these extracts may have the potential to treat Alzheimer's disease with Complex-635 showing more promise.

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