scholarly journals The role of PTB domain containing adaptor proteins on PICALM-mediated APP endocytosis and localization

2019 ◽  
Vol 476 (14) ◽  
pp. 2093-2109 ◽  
Author(s):  
Lisa Merthan ◽  
Amelie Haller ◽  
Dietmar R. Thal ◽  
Bjoern von Einem ◽  
Christine A.F. von Arnim
Keyword(s):  
Cell Surface ◽  
Cell Sorting ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Adaptor Proteins ◽  
Cleavage Product ◽  
Npxy Motif ◽  
Nuclear Shuttling ◽  
Aβ Production

Abstract One hallmark of Alzheimer's disease (AD) is the presence of amyloid plaques, which mainly consist of the amyloid precursor protein (APP) cleavage product amyloid β (Aβ). For cleavage to occur, the APP must be endocytosed from the cell surface. The phosphatidylinositol binding clathrin assembly protein (PICALM) is involved in clathrin-mediated endocytosis and polymorphisms in and near the gene locus were identified as genetic risk factors for AD. PICALM overexpression enhances APP internalization and Aβ production. Furthermore, PICALM shuttles into the nucleus, but its function within the nucleus is still unknown. Using co-immunoprecipitation, we demonstrated an interaction between PICALM and APP, which is abrogated by mutation of the APP NPXY-motif. Since the NPXY-motif is an internalization signal that binds to phosphotryrosine-binding domain-containing adaptor proteins (PTB-APs), we hypothesized that PTB-APs can modulate the APP-PICALM interaction. We found that interaction between PICALM and the PTB-APs (Numb, JIP1b and GULP1) enhances the APP-PICALM interaction. Fluorescence activated cell sorting analysis and internalization assays revealed differentially altered APP cell surface levels and endocytosis rates that depended upon the presence of PICALM and co-expression of distinct PTB-APs. Additionally, we were able to show an impact of PICALM nuclear shuttling upon co-expression of PTB-APs and PICALM, with the magnitude of the effect depending on which PTB-AP was co-expressed. Taken together, our results indicate a modulating effect of PTB-APs on PICALM-mediated APP endocytosis and localization.

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.

scholarly journals The Role of APP O-Glycosylation in Alzheimer’s Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1569
Author(s):  
Keiko Akasaka-Manya ◽  
Hiroshi Manya
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaque ◽  
Amyloid Β ◽  
Pathological Feature ◽  
People With Dementia ◽  
New Findings ◽  
Neurodegenerative Dementia ◽  
Aβ Production

The number of people with dementia is increasing rapidly due to the increase in the aging population. Alzheimer’s disease (AD) is a type of neurodegenerative dementia caused by the accumulation of abnormal proteins. Genetic mutations, smoking, and several other factors have been reported as causes of AD, but alterations in glycans have recently been demonstrated to play a role in AD. Amyloid-β (Aβ), a cleaved fragment of APP, is the source of senile plaque, a pathological feature of AD. APP has been reported to undergo N- and O-glycosylation, and several Polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) have been shown to have catalytic activity for the transfer of GalNAc to APP. Since O-glycosylation in the proximity of a cleavage site in many proteins has been reported to be involved in protein processing, O-glycans may affect the cleavage of APP during the Aβ production process. In this report, we describe new findings on the O-glycosylation of APP and Aβ production.

scholarly journals δ-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Zhentao Zhang ◽  
Ye Tian ◽  
Keqiang Ye
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurological Diseases ◽  
Amyloid Β ◽  
Biochemical Properties ◽  
Aging Brain ◽  
Posttranslational Regulation ◽  
Diagnostic Biomarker ◽  
Protein Substrates ◽  
Aβ Production

AbstractMammalian asparagine endopeptidase (AEP) is a cysteine protease that cleaves its protein substrates on the C-terminal side of asparagine residues. Converging lines of evidence indicate that AEP may be involved in the pathogenesis of several neurological diseases, including Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. AEP is activated in the aging brain, cleaves amyloid precursor protein (APP) and promotes the production of amyloid-β (Aβ). We renamed AEP to δ-secretase to emphasize its role in APP fragmentation and Aβ production. AEP also cleaves other substrates, such as tau, α-synuclein, SET, and TAR DNA-binding protein 43, generating neurotoxic fragments and disturbing their physiological functions. The activity of δ-secretase is tightly regulated at both the transcriptional and posttranslational levels. Here, we review the recent advances in the role of δ-secretase in neurodegenerative diseases, with a focus on its biochemical properties and the transcriptional and posttranslational regulation of its activity, and discuss the clinical implications of δ-secretase as a diagnostic biomarker and therapeutic target for neurodegenerative diseases.

scholarly journals Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains

2016 ◽  
Vol 0 (0) ◽  
Author(s):  
Frederike Schmidt ◽  
Miryam Müller ◽  
Johannes Prox ◽  
Philipp Arnold ◽  
Caroline Schönherr ◽  
...  
Keyword(s):  
Cell Surface ◽  
Transmembrane Protein ◽  
Amyloid Β ◽  
Type I ◽  
Direct Binding ◽  
Small Intestinal ◽  
Split Ubiquitin ◽  
Biological Methods ◽  
Two Hybrid

AbstractMeprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It was shown that meprin β cleaves the amyloid precursor protein (APP), thereby releasing neurotoxic amyloid β peptides and implicating a role of meprin β in Alzheimer’s disease. In order to identify non-proteolytic regulators of meprin β, we performed a split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library. In this screen we identified tetraspanin 8 (TSPAN8) as interaction partner for meprin β. Since several members of the tetraspanin family were described to interact with metalloproteases thereby affecting their localization and/or activity, we hypothesized similar functions of TSPAN8 in the regulation of meprin β. We employed cell biological methods to confirm direct binding of TSPAN8 to meprin β. Surprisingly, we did not observe an effect of TSPAN8 on the catalytic activity of meprin β nor on the specific cleavage of its substrate APP. However, both proteins were identified being present in tetraspanin-enriched microdomains. Therefore we hypothesize that TSPAN8 might be important for the orchestration of meprin β at the cell surface with impact on certain proteolytic processes that have to be further identified.

scholarly journals The Role of Butyrylcholinesterase and Iron in the Regulation of Cholinergic Network and Cognitive Dysfunction in Alzheimer’s Disease Pathogenesis

2021 ◽  
Vol 22 (4) ◽  
pp. 2033
Author(s):  
Jacek Jasiecki ◽  
Monika Targońska ◽  
Bartosz Wasąg
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Iron Homeostasis ◽  
Clinical Signs ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Postmortem Brain ◽  
Brain Iron ◽  
Brain Functions

Alzheimer’s disease (AD), the most common form of dementia in elderly individuals, is marked by progressive neuron loss. Despite more than 100 years of research on AD, there is still no treatment to cure or prevent the disease. High levels of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain are neuropathological hallmarks of AD. However, based on postmortem analyses, up to 44% of individuals have been shown to have high Aβ deposits with no clinical signs, due to having a “cognitive reserve”. The biochemical mechanism explaining the prevention of cognitive impairment in the presence of Aβ plaques is still unknown. It seems that in addition to protein aggregation, neuroinflammatory changes associated with aging are present in AD brains that are correlated with a higher level of brain iron and oxidative stress. It has been shown that iron accumulates around amyloid plaques in AD mouse models and postmortem brain tissues of AD patients. Iron is required for essential brain functions, including oxidative metabolism, myelination, and neurotransmitter synthesis. However, an imbalance in brain iron homeostasis caused by aging underlies many neurodegenerative diseases. It has been proposed that high iron levels trigger an avalanche of events that push the progress of the disease, accelerating cognitive decline. Patients with increased amyloid plaques and iron are highly likely to develop dementia. Our observations indicate that the butyrylcholinesterase (BChE) level seems to be iron-dependent, and reports show that BChE produced by reactive astrocytes can make cognitive functions worse by accelerating the decay of acetylcholine in aging brains. Why, even when there is a genetic risk, do symptoms of the disease appear after many years? Here, we discuss the relationship between genetic factors, age-dependent iron tissue accumulation, and inflammation, focusing on AD.

scholarly journals Presenilin-1 affects trafficking and processing of βAPP and is targeted in a complex with nicastrin to the plasma membrane

2002 ◽  
Vol 158 (3) ◽  
pp. 551-561 ◽  
Author(s):  
Christoph Kaether ◽  
Sven Lammich ◽  
Dieter Edbauer ◽  
Michaela Ertl ◽  
Jens Rietdorf ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Secretory Pathway ◽  
Amyloid Β ◽  
Biologically Active ◽  
Dual Function ◽  
Amyloid Β Peptide ◽  
Secretase Activity ◽  
Β Amyloid ◽  
Aβ Production

Amyloid β-peptide (Aβ) is generated by the consecutive cleavages of β- and γ-secretase. The intramembraneous γ-secretase cleavage critically depends on the activity of presenilins (PS1 and PS2). Although there is evidence that PSs are aspartyl proteases with γ-secretase activity, it remains controversial whether their subcellular localization overlaps with the cellular sites of Aβ production. We now demonstrate that biologically active GFP-tagged PS1 as well as endogenous PS1 are targeted to the plasma membrane (PM) of living cells. On the way to the PM, PS1 binds to nicastrin (Nct), an essential component of the γ-secretase complex. This complex is targeted through the secretory pathway where PS1-bound Nct becomes endoglycosidase H resistant. Moreover, surface-biotinylated Nct can be coimmunoprecipitated with PS1 antibodies, demonstrating that this complex is located to cellular sites with γ-secretase activity. Inactivating PS1 or PS2 function by mutagenesis of one of the critical aspartate residues or by γ-secretase inhibitors results in delayed reinternalization of the β-amyloid precursor protein and its accumulation at the cell surface. Our data suggest that PS is targeted as a biologically active complex with Nct through the secretory pathway to the cell surface and suggest a dual function of PS in γ-secretase processing and in trafficking.

Role of Adaptor Proteins and Clathrin in the Trafficking of Human Kidney Anion Exchanger 1 (kAE1) to the Cell Surface

Traffic ◽  
2014 ◽  
Vol 15 (7) ◽  
pp. 788-802 ◽  
Author(s):  
Mutita Junking ◽  
Nunghathai Sawasdee ◽  
Natapol Duangtum ◽  
Boonyarit Cheunsuchon ◽  
Thawornchai Limjindaporn ◽  
...  
Keyword(s):  
Cell Surface ◽  
Anion Exchanger ◽  
Human Kidney ◽  
Adaptor Proteins ◽  
Anion Exchanger 1

scholarly journals Tetraspanin 8 is an interactor of the metalloprotease meprin β within tetraspanin-enriched microdomains

2016 ◽  
Vol 397 (9) ◽  
pp. 857-869 ◽  
Author(s):  
Frederike Schmidt ◽  
Miryam Müller ◽  
Johannes Prox ◽  
Philipp Arnold ◽  
Caroline Schönherr ◽  
...  
Keyword(s):  
Cell Surface ◽  
Transmembrane Protein ◽  
Amyloid Β ◽  
Type I ◽  
Direct Binding ◽  
Small Intestinal ◽  
Split Ubiquitin ◽  
Biological Methods ◽  
Two Hybrid

Abstract Meprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It has been shown that meprin β cleaves the amyloid precursor protein (APP), thereby releasing neurotoxic amyloid β peptides and implicating a role of meprin β in Alzheimer’s disease. In order to identify non-proteolytic regulators of meprin β, we performed a split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library. In this screen we identified tetraspanin 8 (TSPAN8) as interaction partner for meprin β. As several members of the tetraspanin family were described to interact with metalloproteases thereby affecting their localization and/or activity, we hypothesized similar functions of TSPAN8 in the regulation of meprin β. We employed cell biological methods to confirm direct binding of TSPAN8 to meprin β. Surprisingly, we did not observe an effect of TSPAN8 on the catalytic activity of meprin β nor on the specific cleavage of its substrate APP. However, both proteins were identified as present in tetraspanin-enriched microdomains. Therefore we hypothesize that TSPAN8 might be important for the orchestration of meprin β at the cell surface with impact on certain proteolytic processes that have to be further identified.

The Role of the Interaction between Fe(III) and Cell Surface in the Accumulation of 67Ga by Tumor Cells

1991 ◽  
Vol 30 (06) ◽  
pp. 290-293 ◽  
Author(s):  
P. Maleki ◽  
A. Martinezi ◽  
M. C. Crone-Escanye ◽  
J. Robert ◽  
L. J. Anghileri
Keyword(s):  
Cell Surface ◽  
Tumor Cells ◽  
Ionic Composition ◽  
Iron Complex ◽  
Iron Binding ◽  
Complex Time ◽  
Interaction Product ◽  
Thermodynamic Constant ◽  
Number Of Cells

The study of the interaction between complexed iron and tumor cells in the presence of 67Ga-citrate indicates that a phenomenon of iron-binding related to the thermodynamic constant of stability of the iron complex, and a hydrolysis (or anion penetration) of the interaction product determine the uptake of 67Ga. The effects of various parameters such as ionic composition of the medium, nature of the iron complex, time of incubation and number of cells are discussed.

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