scholarly journals Inhibition of PKCδ reduces amyloid-β levels and reverses Alzheimer disease phenotypes

2018 ◽  
Vol 215 (6) ◽  
pp. 1665-1677 ◽  
Author(s):  
Ying Du ◽  
Yingjun Zhao ◽  
Chuan Li ◽  
Qiuyang Zheng ◽  
Jing Tian ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Β ◽  
Neuritic Plaque ◽  
App Processing ◽  
Disease Phenotypes ◽  
Kinase C ◽  
Bace1 Expression ◽  
Pkc Isoforms ◽  
Exon 9 ◽  
Aβ Generation

β-amyloid protein (Aβ) plays a central role in the pathogenesis of Alzheimer disease (AD). Aβ is generated from sequential cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. Although activation of some protein kinase C (PKC) isoforms such as PKCα and ε has been shown to regulate nonamyloidogenic pathways and Aβ degradation, it is unclear whether other PKC isoforms are involved in APP processing/AD pathogenesis. In this study, we report that increased PKCδ levels correlate with BACE1 expression in the AD brain. PKCδ knockdown reduces BACE1 expression, BACE1-mediated APP processing, and Aβ production. Conversely, overexpression of PKCδ increases BACE1 expression and Aβ generation. Importantly, inhibition of PKCδ by rottlerin markedly reduces BACE1 expression, Aβ levels, and neuritic plaque formation and rescues cognitive deficits in an APP Swedish mutations K594N/M595L/presenilin-1 with an exon 9 deletion–transgenic AD mouse model. Our study indicates that PKCδ plays an important role in aggravating AD pathogenesis, and PKCδ may be a potential target in AD therapeutics.

scholarly journals Identification of Novel γ-Secretase-associated Proteins in Detergent-resistant Membranes from Brain

2012 ◽  
Vol 287 (15) ◽  
pp. 11991-12005 ◽  
Author(s):  
Ji-Yeun Hur ◽  
Yasuhiro Teranishi ◽  
Takahiro Kihara ◽  
Natsuko Goto Yamamoto ◽  
Mitsuhiro Inoue ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Affinity Purification ◽  
Amyloid Β ◽  
Anion Channel ◽  
Amyloid Β Peptide ◽  
Voltage Dependent Anion Channel ◽  
App Processing ◽  
Associated Proteins ◽  
Detergent Resistant Membranes ◽  
Aβ Production

In Alzheimer disease, oligomeric amyloid β-peptide (Aβ) species lead to synapse loss and neuronal death. γ-Secretase, the transmembrane protease complex that mediates the final catalytic step that liberates Aβ from its precursor protein (APP), has a multitude of substrates, and therapeutics aimed at reducing Aβ production should ideally be specific for APP cleavage. It has been shown that APP can be processed in lipid rafts, and γ-secretase-associated proteins can affect Aβ production. Here, we use a biotinylated inhibitor for affinity purification of γ-secretase and associated proteins and mass spectrometry for identification of the purified proteins, and we identify novel γ-secretase-associated proteins in detergent-resistant membranes from brain. Furthermore, we show by small interfering RNA-mediated knockdown of gene expression that a subset of the γ-secretase-associated proteins, in particular voltage-dependent anion channel 1 (VDAC1) and contactin-associated protein 1 (CNTNAP1), reduced Aβ production (Aβ40 and Aβ42) by around 70%, whereas knockdown of presenilin 1, one of the essential γ-secretase complex components, reduced Aβ production by 50%. Importantly, these proteins had a less pronounced effect on Notch processing. We conclude that VDAC1 and CNTNAP1 associate with γ-secretase in detergent-resistant membranes and affect APP processing and suggest that molecules that interfere with this interaction could be of therapeutic use for Alzheimer disease.

scholarly journals Altered Amyloid-β Metabolism and Deposition in Genomic-based β-Secretase Transgenic Mice

2004 ◽  
Vol 279 (50) ◽  
pp. 52535-52542 ◽  
Author(s):  
Matthew J. Chiocco ◽  
Laura Shapiro Kulnane ◽  
Linda Younkin ◽  
Steve Younkin ◽  
Geneviève Evin ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Transgenic Animals ◽  
Brain Regions ◽  
Primary Component ◽  
App Processing ◽  
Bace1 Expression ◽  
First Time

Amyloid-β (Aβ) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by β-secretase followed by γ-secretase cleavage. Identification of the primary β-secretase gene,BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering Aβ metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating β-secretase expression and activity alters APP processing and Aβ metabolismin vivo. Genomic-basedBACE1transgenic mice were generated that overexpress humanBACE1mRNA and protein. The highest expressingBACE1transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing bothBACE1andAPPshow specific alterations in APP processing and age-dependent Aβ deposition. We observed elevated levels of Aβ isoforms as well as significant increases of Aβ deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for β-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation ofBACE1activity may play a significant role in AD pathogenesisin vivo.

scholarly journals NRF2/ARE pathway negatively regulates BACE1 expression and ameliorates cognitive deficits in mouse Alzheimer’s models

2019 ◽  
Vol 116 (25) ◽  
pp. 12516-12523 ◽  
Author(s):  
Gahee Bahn ◽  
Jong-Sung Park ◽  
Ui Jeong Yun ◽  
Yoon Jee Lee ◽  
Yuri Choi ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Redox Regulation ◽  
Amyloid Β ◽  
Antioxidant Response ◽  
Related Factor ◽  
Bace1 Expression ◽  
Nrf2 Activation ◽  
Antioxidant Response Elements ◽  
Aβ Generation ◽  
Aβ Production

BACE1 is the rate-limiting enzyme for amyloid-β peptides (Aβ) generation, a key event in the pathogenesis of Alzheimer’s disease (AD). By an unknown mechanism, levels of BACE1 and a BACE1 mRNA-stabilizing antisense RNA (BACE1-AS) are elevated in the brains of AD patients, implicating that dysregulation of BACE1 expression plays an important role in AD pathogenesis. We found that nuclear factor erythroid-derived 2-related factor 2 (NRF2/NFE2L2) represses the expression of BACE1 and BACE1-AS through binding to antioxidant response elements (AREs) in their promoters of mouse and human. NRF2-mediated inhibition of BACE1 and BACE1-AS expression is independent of redox regulation. NRF2 activation decreases production of BACE1 and BACE1-AS transcripts and Aβ production and ameliorates cognitive deficits in animal models of AD. Depletion of NRF2 increases BACE1 and BACE1-AS expression and Aβ production and worsens cognitive deficits. Our findings suggest that activation of NRF2 can prevent a key early pathogenic process in AD.

scholarly journals The cellular expression and proteolytic processing of the amyloid precursor protein is independent of TDP-43

2020 ◽  
Vol 40 (4) ◽  
Author(s):  
David A. Hicks ◽  
Alys C. Jones ◽  
Stuart M. Pickering-Brown ◽  
Nigel M. Hooper
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Aβ Peptides ◽  
App Processing ◽  
Cellular Expression ◽  
Aβ Generation ◽  
Human Neuronal Cells ◽  
Inducible Cell Line

Abstract Alzheimer’s disease (AD) is a neurodegenerative condition, of which one of the cardinal pathological hallmarks is the extracellular accumulation of amyloid β (Aβ) peptides. These peptides are generated via proteolysis of the amyloid precursor protein (APP), in a manner dependent on the β-secretase, BACE1 and the multicomponent γ-secretase complex. Recent data also suggest a contributory role in AD of transactive response DNA binding protein 43 (TDP-43). There is little insight into a possible mechanism linking TDP-43 and APP processing. To this end, we used cultured human neuronal cells to investigate the ability of TDP-43 to interact with APP and modulate its proteolytic processing. Immunocytochemistry showed TDP-43 to be spatially segregated from both the extranuclear APP holoprotein and its nuclear C-terminal fragment. The latter (APP intracellular domain) was shown to predominantly localise to nucleoli, from which TDP-43 was excluded. Furthermore, neither overexpression of each of the APP isoforms nor siRNA-mediated knockdown of APP had any effect on TDP-43 expression. Doxycycline-stimulated overexpression of TDP-43 was explored in an inducible cell line. Overexpression of TDP-43 had no effect on expression of the APP holoprotein, nor any of the key proteins involved in its proteolysis. Furthermore, increased TDP-43 expression had no effect on BACE1 enzymatic activity or immunoreactivity of Aβ1-40, Aβ1-42 or the Aβ1-40:Aβ1-42 ratio. Also, siRNA-mediated knockdown of TDP-43 had no effect on BACE1 immunoreactivity. Taken together, these data indicate that TDP-43 function and/or dysfunction in AD is likely independent from dysregulation of APP expression and proteolytic processing and Aβ generation.

scholarly journals The intact Kunitz domain protects the amyloid precursor protein from being processed by matriptase-2

2016 ◽  
Vol 397 (8) ◽  
pp. 777-790 ◽  
Author(s):  
Anna-Madeleine Beckmann ◽  
Konstantin Glebov ◽  
Jochen Walter ◽  
Olaf Merkel ◽  
Martin Mangold ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Iron Homeostasis ◽  
Amyloid Β ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
App Processing ◽  
Kunitz Domain ◽  
Membrane Bound ◽  
Aβ Generation ◽  
Slow Binding Inhibitor

Abstract Proteolytic processing of the amyloid precursor protein (APP) leads to amyloid-β (Aβ) peptides. So far, the mechanism of APP processing is insufficiently characterized at the molecular level. Whereas the knowledge of Aβ generation by several proteases has been expanded, the contribution of the Kunitz-type protease inhibitor domain (KPI) present in two major APP isoforms to the complex proteolytic processing of APP is poorly understood. In this study, we have identified KPI-containing APP as a very potent, slow-binding inhibitor for the membrane-bound proteolytic regulator of iron homeostasis matriptase-2 by forming stable complexes with its target protease in HEK cells. Inhibition and complex formation depend on the intact KPI domain. By inhibiting matriptase-2, KPI-containing APP is protected from matriptase-2-mediated proteolysis within the Aβ region, thus preventing the generation of N-terminally truncated Aβ.

scholarly journals Effect of Caffeine and Other Methylxanthines on Aβ-Homeostasis in SH-SY5Y Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 689 ◽  
Author(s):  
Daniel Janitschke ◽  
Christopher Nelke ◽  
Anna Lauer ◽  
Liesa Regner ◽  
Jakob Winkler ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Mechanisms Of Action ◽  
Point Of View ◽  
Purine Base ◽  
App Processing ◽  
Naturally Occurring ◽  
Secretase Activity ◽  
Bace1 Expression

Methylxanthines (MTX) are alkaloids derived from the purine-base xanthine. Whereas especially caffeine, the most prominent known MTX, has been formerly assessed to be detrimental, this point of view has changed substantially. MTXs are discussed to have beneficial properties in neurodegenerative diseases, however, the mechanisms of action are not completely understood. Here we investigate the effect of the naturally occurring caffeine, theobromine and theophylline and the synthetic propentofylline and pentoxifylline on processes involved in Alzheimer’s disease (AD). All MTXs decreased amyloid-β (Aβ) level by shifting the amyloid precursor protein (APP) processing from the Aβ-producing amyloidogenic to the non-amyloidogenic pathway. The α-secretase activity was elevated whereas β-secretase activity was decreased. Breaking down the molecular mechanism, caffeine increased protein stability of the major α-secretase ADAM10, downregulated BACE1 expression and directly decreased β-secretase activity. Additionally, APP expression was reduced. In line with literature, MTXs reduced oxidative stress, decreased cholesterol and a decreased in Aβ1-42 aggregation. In conclusion, all MTXs act via the pleiotropic mechanism resulting in decreased Aβ and show beneficial properties with respect to AD in neuroblastoma cells. However, the observed effect strength was moderate, suggesting that MTXs should be integrated in a healthy diet rather than be used exclusively to treat or prevent AD.

scholarly journals APP processing is regulated by cytoplasmic phosphorylation

2003 ◽  
Vol 163 (1) ◽  
pp. 83-95 ◽  
Author(s):  
Ming-Sum Lee ◽  
Shih-Chu Kao ◽  
Cynthia A. Lemere ◽  
Weiming Xia ◽  
Huang-Chun Tseng ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Kinase Inhibitors ◽  
Senile Plaque ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Hippocampal Pyramidal Neurons ◽  
App Processing ◽  
App Metabolism ◽  
Aβ Generation

Amyloid-β peptide (Aβ) aggregate in senile plaque is a key characteristic of Alzheimer's disease (AD). Here, we show that phosphorylation of amyloid precursor protein (APP) on threonine 668 (P-APP) may play a role in APP metabolism. In AD brains, P-APP accumulates in large vesicular structures in afflicted hippocampal pyramidal neurons that costain with antibodies against endosome markers and the β-secretase, BACE1. Western blot analysis reveals increased levels of T668-phosphorylated APP COOH-terminal fragments in hippocampal lysates from many AD but not control subjects. Importantly, P-APP cofractionates with endosome markers and BACE1 in an iodixanol gradient and displays extensive colocalization with BACE1 in rat primary cortical neurons. Furthermore, APP COOH-terminal fragments generated by BACE1 are preferentially phosphorylated on T668 verses those produced by α-secretase. The production of Aβ is significantly reduced when phosphorylation of T668 is either abolished by mutation or inhibited by T668 kinase inhibitors. Together, these results suggest that T668 phosphorylation may facilitate the BACE1 cleavage of APP to increase Aβ generation.

Structural and Chemical Studies of Pathological Fibers in Human Neurofibrillary Degeneration

1985 ◽  
Vol 43 ◽  
pp. 726-729
Author(s):  
K.S. Kosik ◽  
L.K. Duffy ◽  
S. Bakalis ◽  
C. Abraham ◽  
D.J. Selkoe
Keyword(s):  
Monoclonal Antibodies ◽  
Alzheimer Disease ◽  
Human Brain ◽  
Neurofibrillary Tangles ◽  
Morphological Analysis ◽  
High Specificity ◽  
Cytoskeletal Proteins ◽  
Neuritic Plaque ◽  
Protein Chemistry ◽  
Chemical Studies

The major structural lesions of the human brain during aging and in Alzheimer disease (AD) are the neurofibrillary tangles (NFT) and the senile (neuritic) plaque. Although these fibrous alterations have been recognized by light microscopists for almost a century, detailed biochemical and morphological analysis of the lesions has been undertaken only recently. Because the intraneuronal deposits in the NFT and the plaque neurites and the extraneuronal amyloid cores of the plaques have a filamentous ultrastructure, the neuronal cytoskeleton has played a prominent role in most pathogenetic hypotheses.The approach of our laboratory toward elucidating the origin of plaques and tangles in AD has been two-fold: the use of analytical protein chemistry to purify and then characterize the pathological fibers comprising the tangles and plaques, and the use of certain monoclonal antibodies to neuronal cytoskeletal proteins that, despite high specificity, cross-react with NFT and thus implicate epitopes of these proteins as constituents of the tangles.

scholarly journals Shotgun lipidomics of liver and brain tissue of Alzheimer’s disease model mice treated with acitretin

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna A. Lauer ◽  
Daniel Janitschke ◽  
Malena dos Santos Guilherme ◽  
Vu Thu Thuy Nguyen ◽  
Cornel M. Bachmann ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Lipid Homeostasis ◽  
Medical Surveillance ◽  
Shotgun Lipidomics ◽  
App Processing ◽  
Cognitive Improvement ◽  
The Impact

AbstractAlzheimer’s disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients.

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