scholarly journals A cell-permeable tool for analysing APP intracellular domain function and manipulation of PIKfyve activity

2016 ◽  
Vol 36 (2) ◽  
Author(s):  
Benjamin Guscott ◽  
Zita Balklava ◽  
Stephen T. Safrany ◽  
Thomas Wassmer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Intracellular Domain ◽  
Central Molecule ◽  
A Cell

In this work we developed and validated a cell permeable tool to study the intracellular function of a central molecule in Alzheimer's disease, the amyloid precursor protein. We showed that it regulates the activity of the PIKfyve kinase complex.

scholarly journals The Amyloid Precursor Protein Intracellular Domain-Fe65 Multiprotein Complexes: A Challenge to the Amyloid Hypothesis for Alzheimer's Disease?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Daniel A. Bórquez ◽  
Christian González-Billault
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Molecular Mechanisms ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Intracellular Domain ◽  
Multiprotein Complexes ◽  
Amyloid Cascade

Since its proposal in 1994, the amyloid cascade hypothesis has prevailed as the mainstream research subject on the molecular mechanisms leading to the Alzheimer's disease (AD). Most of the field had been historically based on the role of the different forms of aggregation ofβ-amyloid peptide (Aβ). However, a soluble intracellular fragment termed amyloid precursor protein (APP) intracellular domain (AICD) is produced in conjunction with Aβfragments. This peptide had been shown to be highly toxic in both culture neurons and transgenic mice models. With the advent of this new toxic fragment, the centerpiece for the ethiology of the disease may be changed. This paper discusses the potential role of multiprotein complexes between the AICD and its adapter protein Fe65 and how this could be a potentially important new agent in the neurodegeneration observed in the AD.

scholarly journals The Amyloid Precursor Protein (APP) Family Members are Key Players in S-adenosylmethionine Formation by MAT2A and Modify BACE1 and PSEN1 Gene Expression-Relevance for Alzheimer's Disease

2012 ◽  
Vol 11 (11) ◽  
pp. 1274-1288 ◽  
Author(s):  
Andreas Schrötter ◽  
Kathy Pfeiffer ◽  
Fouzi El Magraoui ◽  
Harald W. Platta ◽  
Ralf Erdmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Senile Plaques ◽  
Mrna Level ◽  
Family Members ◽  
Precursor Protein ◽  
A Cell ◽  
Psen1 Gene

Central hallmark of Alzheimer's disease are senile plaques mainly composed of β-amyloid, which is a cleavage product of the amyloid precursor protein (APP). The physiological function of APP and its family members APLP1 and APLP2 is poorly understood. In order to fill this gap, we established a cell-culture based model with simultaneous knockdown of all members of the family. A comprehensive proteome study of the APP/APLP1/APLP2 knockdown cell lysates versus controls revealed significant protein abundance changes of more than 30 proteins. Targeted validation of selected candidates by immunoblotting supported the significant down-regulation of the methionine adenosyltransferase II, alpha (MAT2A) as well as of peroxiredoxin 4 in the knockdown cells. Moreover, MAT2A was significantly down-regulated at the mRNA level as well. MAT2A catalyzes the production of S-adenosylmethionine from methionine and ATP, which plays a pivotal role in the methylation of neurotransmitters, DNA, proteins, and lipids. MAT2A-dependent significant up-regulation of S-adenosylmethionine was also detectable in the knockdown cells compared with controls. Our results point to a role of the APP family proteins in cellular methylation mechanisms and fit to findings of disturbed S-adenosylmethionine levels in tissue and CSF of Alzheimer disease patients versus controls. Importantly, methylation plays a central role for neurotransmitter generation like acetylcholine pointing to a crucial relevance of our findings for Alzheimer's disease. In addition, we identified differential gene expression of BACE1 and PSEN1 in the knockdown cells, which is possibly a consequence of MAT2A deregulation and may indicate a self regulatory mechanism.

scholarly journals Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin

2007 ◽  
Vol 18 (9) ◽  
pp. 3591-3600 ◽  
Author(s):  
Yvonne S. Eisele ◽  
Matthias Baumann ◽  
Bert Klebl ◽  
Christina Nordhammer ◽  
Mathias Jucker ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Kinase Inhibitor ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Intracellular Domain ◽  
Degrading Enzyme ◽  
Protein Levels

Amyloid-β (Aβ) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower Aβ secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases Aβ levels without the inhibition of Notch cleavage by a mechanism distinct from γ-secretase inhibition. Gleevec does not influence γ-secretase activity in vitro; however, treatment of cell lines leads to a dose-dependent increase in the amyloid precursor protein intracellular domain (AICD), whereas secreted Aβ is decreased. This effect is observed even in presence of a potent γ-secretase inhibitor, suggesting that Gleevec does not activate AICD generation but instead may slow down AICD turnover. Concomitant with the increase in AICD, Gleevec leads to elevated mRNA and protein levels of the Aβ-degrading enzyme neprilysin, a potential target gene of AICD-regulated transcription. Thus, the Gleevec mediated-increase in neprilysin expression may involve enhanced AICD signaling. The finding that Gleevec elevates neprilysin levels suggests that its Aβ-lowering effect may be caused by increased Aβ-degradation.

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

Exploring the Role of Aggregated Proteomes in the Pathogenesis of Alzheimer’s Disease

2020 ◽  
Vol 21 (12) ◽  
pp. 1164-1173
Author(s):  
Siju Ellickal Narayanan ◽  
Nikhila Sekhar ◽  
Rajalakshmi Ganesan Rajamma ◽  
Akash Marathakam ◽  
Abdullah Al Mamun ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Early Onset ◽  
Late Onset ◽  
Precursor Protein ◽  
Brain Disorder ◽  
Amyloid Aβ ◽  
T Tau

: Alzheimer’s disease (AD) is a progressive brain disorder and one of the most common causes of dementia and death. AD can be of two types; early-onset and late-onset, where late-onset AD occurs sporadically while early-onset AD results from a mutation in any of the three genes that include amyloid precursor protein (APP), presenilin 1 (PSEN 1) and presenilin 2 (PSEN 2). Biologically, AD is defined by the presence of the distinct neuropathological profile that consists of the extracellular β-amyloid (Aβ) deposition in the form of diffuse neuritic plaques, intraneuronal neurofibrillary tangles (NFTs) and neuropil threads; in dystrophic neuritis, consisting of aggregated hyperphosphorylated tau protein. Elevated levels of (Aβ), total tau (t-tau) and phosphorylated tau (ptau) in cerebrospinal fluid (CSF) have become an important biomarker for the identification of this neurodegenerative disease. The aggregation of Aβ peptide derived from amyloid precursor protein initiates a series of events that involve inflammation, tau hyperphosphorylation and its deposition, in addition to synaptic dysfunction and neurodegeneration, ultimately resulting in dementia. The current review focuses on the role of proteomes in the pathogenesis of AD.

Sign in / Sign up

Export Citation Format

Share Document