Identification of Novel Small Molecule Inhibitors of Amyloid Precursor Protein Synthesis as a Route to Lower Alzheimer's Disease Amyloid-β Peptide

2006 ◽  
Vol 318 (2) ◽  
pp. 855-862 ◽  
Author(s):  
Tada Utsuki ◽  
Qian-sheng Yu ◽  
Diane Davidson ◽  
Demao Chen ◽  
Harold W. Holloway ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Synthesis ◽  
Amyloid Precursor Protein ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Amyloid Precursor Protein Synthesis

Protein–protein interactions in the assembly and subcellular trafficking of the BACE (β-site amyloid precursor protein-cleaving enzyme) complex of Alzheimer's disease

2007 ◽  
Vol 35 (5) ◽  
pp. 974-979 ◽  
Author(s):  
R.B. Parsons ◽  
B.M. Austen
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Protein Interactions ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Aβ Amyloid ◽  
Ad Alzheimer’S Disease

The correct assembly of the BACE (β-site amyloid precursor protein-cleaving enzyme or β-secretase) complex and its subsequent trafficking to cellular compartments where it associates with the APP (amyloid precursor protein) is essential for the production of Aβ (amyloid β-peptide), the protein whose aggregation into senile plaques is thought to be responsible for the pathogenesis of AD (Alzheimer's disease). These processes rely upon both transient and permanent BACE–protein interactions. This review will discuss what is currently known about these BACE–protein interactions and how they may reveal novel therapeutic targets for the treatment of AD.

scholarly journals A novel mechanism for the regulation of amyloid precursor protein metabolism

2002 ◽  
Vol 158 (1) ◽  
pp. 79-89 ◽  
Author(s):  
Qi Chen ◽  
Hideo Kimura ◽  
David Schubert
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Amyloid Precursor Protein ◽  
Proteasome Inhibitors ◽  
Amyloid Β ◽  
Cellular Adhesion ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
App Processing

Modifier of cell adhesion protein (MOCA; previously called presenilin [PS] binding protein) is a DOCK180-related molecule, which interacts with PS1 and PS2, is localized to brain areas involved in Alzheimer's disease (AD) pathology, and is lost from the soluble fraction of sporadic Alzheimer's disease (AD) brains. Because PS1 has been associated with γ-secretase activity, MOCA may be involved in the regulation of β-amyloid precursor protein (APP) processing. Here we show that the expression of MOCA decreases both APP and amyloid β-peptide secretion and lowers the rate of cell-substratum adhesion. In contrast, MOCA does not lower the secretion of amyloid precursor-like protein (APLP) or several additional type 1 membrane proteins. The phenotypic changes caused by MOCA are due to an acceleration in the rate of intracellular APP degradation. The effect of MOCA expression on the secretion of APP and cellular adhesion is reversed by proteasome inhibitors, suggesting that MOCA directs nascent APP to proteasomes for destruction. It is concluded that MOCA plays a major role in APP metabolism and that the effect of MOCA on APP secretion and cell adhesion is a downstream consequence of MOCA-directed APP catabolism. This is a new mechanism by which the expression of APP is regulated.

The Alzheimer's Disease Amyloid Precursor Protein and its Neuritogenic Actions

2021 ◽  
Vol 18 ◽  
Author(s):  
Luan Luu ◽  
Giuseppe D. Ciccotosto ◽  
Roberto Cappai
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nervous System ◽  
Amyloid Precursor Protein ◽  
Molecular Mechanisms ◽  
Amyloid Β ◽  
Normal Function ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Neuronal Functions

: The Amyloid Precursor Protein (APP) is principally known and studied for its involve- ment in Alzheimer’s disease as the source of the amyloid β peptide; however, its physiological ac- tions within the nervous system are also important as it is involved in a range of neuronal activi- ties, including neurogenesis, synaptic plasticity, neurite outgrowth, and neuroprotection. Of the dif- ferent neuronal functions that APP can affect, some may be relevant to APP’s role in Alzheimer’s disease, while others can be primarily related to its physiological roles. This review will focus on APP’s neuritogenic actions and surmise the key molecular mechanisms, as well as the structural and signaling requirements, which form the basis for APP’s neuritogenic effects. Deciphering the normal function(s) of APP is valuable to properly understanding its role in health as well as Alzheimer’s disease.

Impact of Vitamin D on Amyloid Precursor Protein Processing and Amyloid-β Peptide Degradation in Alzheimer's Disease

2013 ◽  
Vol 13 (2-3) ◽  
pp. 75-81 ◽  
Author(s):  
Marcus O.W. Grimm ◽  
Johannes Lehmann ◽  
Janine Mett ◽  
Valerie C. Zimmer ◽  
Sven Grösgen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Vitamin D ◽  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Protein Processing ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Peptide ◽  
Peptide Degradation

A Numerical Study of Sensitivity Coefficients for a Model of Amyloid Precursor Protein and Tubulin-Associated Unit Protein Transport and Agglomeration in Neurons at the Onset of Alzheimer's Disease

2019 ◽  
Vol 141 (3) ◽  
Author(s):  
I. A. Kuznetsov ◽  
A. V. Kuznetsov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Tau Protein ◽  
Protein Transport ◽  
Numerical Study ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Model Parameters ◽  
In The Beginning

Modeling of intracellular processes occurring during the development of Alzheimer's disease (AD) can be instrumental in understanding the disease and can potentially contribute to finding treatments for the disease. The model of intracellular processes in AD, which we previously developed, contains a large number of parameters. To distinguish between more important and less important parameters, we performed a local sensitivity analysis of this model around the values of parameters that give the best fit with published experimental results. We show that the influence of model parameters on the total concentrations of amyloid precursor protein (APP) and tubulin-associated unit (tau) protein in the axon is reciprocal to the influence of the same parameters on the average velocities of the same proteins during their transport in the axon. The results of our analysis also suggest that in the beginning of AD the aggregation of amyloid-β and misfolded tau protein have little effect on transport of APP and tau in the axon, which suggests that early damage in AD may be reversible.

scholarly journals Pyk2 overexpression in postsynaptic neurons blocks amyloid β1–42-induced synaptotoxicity in microfluidic co-cultures

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Devrim Kilinc ◽  
Anaïs-Camille Vreulx ◽  
Tiago Mendes ◽  
Amandine Flaig ◽  
Diego Marques-Coelho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Genetic Risk ◽  
Association Studies ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Genome Wide Association Studies ◽  
Risk Genes ◽  
The Impact

Abstract Recent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer’s disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer’s disease, deciphering the impact of Alzheimer’s risk genes on synapse formation and maintenance is of great interest. In this article, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid β peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein. Co-culture with cells overexpressing mutated amyloid precursor protein exposed the synapses of primary hippocampal neurons to amyloid β1–42 molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of amyloid β suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta—an Alzheimer’s disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimer’s disease brains at gene expression and protein levels—selectively in postsynaptic neurons is protective against amyloid β1–42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically relevant model of Alzheimer’s disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments.

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