Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease

Svedružić, Željko M.; Popović, Katarina; Šendula-Jengić, Vesna

doi:10.1016/j.mcn.2015.06.002

Cited by 15 publications

(47 citation statements)

References 49 publications

(240 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genetic variants are classified as pathogenic, probably pathogenic, variant of unknown significance, probably non-pathogenic and benign. In case of Lynch syndrome, pathogenic variants are identified by describing family histories of breast or ovarian cancer while benign variants are independent of family history [54]. Several genetic databases are available online that proved to be helpful in determining the type of genetic variant [55].…”

Section: Classification Of Genetic Variation On the Basis Of Pathogenmentioning

confidence: 99%

Genetic Variations: Heroes or Villains

Kaushik¹,

Chaudhary²,

Mahendru³

2016

J Down Syndr Chr Abnorm

View full text Add to dashboard Cite

Gene pool of every organism has shown a wide occurrence of genetic variations. Variations have not only been associated with diseases like cancer, turner syndrome, sickle cell anaemia, cystic fibrosis etc., but some of them have even been proved to be beneficial in certain cases like for increasing bone density, lowering down cholesterol level, and for developing malaria resistance. Genetic variations or switches have also been explored for their significant role in evolution of human species. Monogenic diseases are the inherited disorders caused by the mutations in a single gene. Single Nucleotide Polymorphism, structural variants and genomic rearrangements are considered as some of the forms of genetic mutations. Genetic mutations are the fundamental cause of some monogenic disorders such as Schizophrenia, Alzheimer's disease, Hutchinson-Gilford Progeria syndrome (HGPS), Proteus syndrome and Congenital generalized hypertrichosis (CGH). However, some variants have even offered protection against a disease like blocking of HIV infection due to mutations in co-receptors needed for entry of infection into the cells. This review aims to provide insights into the role of variants present in the genes associated with the monogenic disorders in order to determine the underlying mechanism of the disease, which might further pave a way for the scientists to discover the therapeutic approaches for dealing with the same.

show abstract

Section: Classification Of Genetic Variation On the Basis Of Pathogenmentioning

confidence: 99%

Genetic Variations: Heroes or Villains

Kaushik¹,

Chaudhary²,

Mahendru³

2016

J Down Syndr Chr Abnorm

View full text Add to dashboard Cite

show abstract

“…A large number of repeated failures in the last twenty years have led to numerous proposals that γ-secretase might not be a good therapeutic target (2)(3)(4)(5). An alternative, less frequently considered explanation, is that a very few of the failed drug-design strategies, have taken into account the complexity of the catalytic mechanism of γ-secretase (2,(4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

“…Biphasic dose-response can be observed in cell-cultures (8,10,12,15), in model animals (8,14), and in patient´s plasma in clinical trials (9). The biphasic dose-response can be observed only in studies that use physiological sub-saturating substrate concentrations, and a full concertation range for the drugs (7)(8)(9)(10). It is very likely, that all types of drugs that target presenilin subunit of γsecretase, can produce the biphasic dose-response when Aβ metabolism is at the physiological level (6,8,9,12).…”

Section: Introductionmentioning

confidence: 99%

“…However, the "fast-and-cheap" approach is also the main reason why the majority of the preclinical studies were misleading, or had poor relevance to the clinical studies (2,4,6,8,9,13,14). γ-Secretase is far from saturation with its substrate in physiological conditions in cells (7,8,10,14), just as the majority of other enzymes (16,19,20). Sub saturated enzymes are a fundamental physiological mechanism, that can assure the fastest, and bestcontrolled responses to metabolic changes (16,19).…”

Section: Introductionmentioning

confidence: 99%

“…The initial mechanistic studies showed that the biphasic dose-response drugs can produce the same type of changes in γ-secretase activity as the disease-causing FAD mutations (7,23). Both, FAD mutation and the biphasic-drugs, can cause accumulation of the longer and more hydrophobic Aβ products (6,12,21,24,25).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural Analysis of Simultaneous Activation and Inhibition of γ-Secretase Activity in Development of Drugs for Alzheimer’s disease

Svedružić

Vrbnjak

Martinović

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Significance: The majority of drugs that target membrane-embedded protease gamma-secretase show unusual biphasic activation-inhibition dose-response in cells, model animals, and humans. Semagacestat and avagacestat are two biphasic-drugs that can facilitate cognitive decline in patients with Alzheimers disease. Initial mechanistic studies showed that the biphasic-drugs, and pathogenic mutations, can produce the same type of changes in γ-secretase activity. Results: DAPT, semagacestat LY-411,575, and avagacestat are four drugs that show different binding constants, and biphasic activation-inhibition dose-response curves, for amyloid-beta-40 products in SHSY-5 cells. Multiscale molecular dynamics studies showed that all four drugs bind to the most mobile parts in presenilin structure, at different ends of the 29 A long active site tunnel. Combined results from structure-activity studies, showed that the biphasic dose-response curves are a result of modulation of gamma-secretase activity by concurrent binding of multiple drug molecules at each end of the active site tunnel. The drugs activate gamma-secretase by forcing the active site tunnel to open, when the rate-limiting step is the tunnel opening, and formation of the enzyme-substrate complex. The drugs inhibit gamma-secretase as uncompetitive inhibitors, by binding next to the substrate to dynamic enzyme structures that regulate processive catalysis. The drugs can modulate the production of different amyloid-beta catalytic intermediates, by penetrating into the active site tunnel to different depth with different binding affinity. The drugs and pathogenic mutations affect the same dynamic processes in gamma-secretase structure. Conclusions: Biphasic-drugs like disease-causing mutations can reduce the catalytic capacity of gamma-secretase and facilitate pathogenic changes in amyloid metabolism.

show abstract

Strain-Specific Altered Regulatory Response of Rab7a and Tau in Creutzfeldt-Jakob Disease and Alzheimer’s Disease

Zafar¹,

Younas²,

Correia³

et al. 2016

Mol Neurobiol

View full text Add to dashboard Cite

There is an increasing demand for the understanding of pathophysiology on neurodegeneration diseases at early stages. Changes in endocytic machinery and the cytoskeleton-associated response are the first alterations observed in Creutzfeldt-Jakob disease (CJD) and Alzheimer's disease AD brain. In this study, we performed a targeted search for endocytic pathway proteins in the different regions of the brain. We found late endosome marker Rab7a which was significantly upregulated in the frontal cortex region in the rapid progressive CJD form (MM1) and rapid progressive AD (rpAD) forms. However, Rab9 expression was significantly downregulated only in CJD-MM1 brain frontal cortex region. In the cerebellum, Rab7a expression showed significant upregulation in both subtype MM1 and VV2 CJD forms, in contrast to Rab9 which showed significant downregulation in both subtype MM1 and VV2 CJD forms at terminal stage of the disease. To check regulatory response at pre-symptomatic stage of the disease, we checked the regulatory interactive response of Rab7a, Rab9, and known biomarkers PrP and tau forms in frontal cortex at pre-symptomatic stage of the disease in tg340 mice expressing about fourfold of human PrP-M129 with PrP-null background that had been inoculated with human sCJD MM1 brain tissue homogenates (sCJD MM1 mice). In addition, we analyzed 5XFAD mice, exhibiting five mutations in the APP and presenilin genes related to familial Alzheimer's disease (FAD), to validate specific regulatory response of Rab7a, Rab9, tau, and phosphorylated form of tau by immunostaining 5XFAD mice in comparison with the wild-type age-matched mice brain. The cortical region of 5XFAD mice brain showed accumulated form of Rab7a in puncta that co-label for p-Tau, indicating colocalization by using confocal laser-scanning microscopy and was confirmed by using reverse co-immunoprecipitation. Furthermore, synthetic RNA (siRNA) against the Rab7a gene decreased expression of Rab7a protein, in cortical primary neuronal cultures of PrP wild type. This depleted expression of Rab7a led to the increased accumulation of PrP in Rab9-positive endosomal compartments and consequently an increased co-localization between PrP/Rab9; however, total tau level decreased. Interestingly, siRNA against tau gene in cortical primary neuronal cultures of PrP wild-type mice showed enhanced Rab7a and Rab9 expression and increase formation of dendritic spines. The work described highlighted the selective involvement of late endosomal compartment marker Rab7a in CJD, slow and rapid progressive forms of AD pathogenesis.

show abstract

Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease

Cited by 15 publications

References 49 publications

Genetic Variations: Heroes or Villains

Genetic Variations: Heroes or Villains

Structural Analysis of Simultaneous Activation and Inhibition of γ-Secretase Activity in Development of Drugs for Alzheimer’s disease

Strain-Specific Altered Regulatory Response of Rab7a and Tau in Creutzfeldt-Jakob Disease and Alzheimer’s Disease

Contact Info

Product

Resources

About