scholarly journals Mitochondrial targeting and a novel transmembrane arrest of Alzheimer's amyloid precursor protein impairs mitochondrial function in neuronal cells

2003 ◽  
Vol 161 (1) ◽  
pp. 41-54 ◽  
Author(s):  
Hindupur K. Anandatheerthavarada ◽  
Gopa Biswas ◽  
Marie-Anne Robin ◽  
Narayan G. Avadhani
Keyword(s):  
Amyloid Precursor Protein ◽  
Neuronal Cells ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Mitochondrial Targeting ◽  
Acidic Domain ◽  
Targeting Signal ◽  
Critical Components ◽  
First Time ◽  
Positively Charged

Alzheimer's amyloid precursor protein 695 (APP) is a plasma membrane protein, which is known to be the source of the toxic amyloid β (Aβ) peptide associated with the pathogenesis of Alzheimer's disease (AD). Here we demonstrate that by virtue of its chimeric NH2-terminal signal, APP is also targeted to mitochondria of cortical neuronal cells and select regions of the brain of a transgenic mouse model for AD. The positively charged residues at 40, 44, and 51 of APP are critical components of the mitochondrial-targeting signal. Chemical cross-linking together with immunoelectron microscopy show that the mitochondrial APP exists in NH2-terminal inside transmembrane orientation and in contact with mitochondrial translocase proteins. Mutational studies show that the acidic domain, which spans sequence 220–290 of APP, causes the transmembrane arrest with the COOH-terminal 73-kD portion of the protein facing the cytoplasmic side. Accumulation of full-length APP in the mitochondrial compartment in a transmembrane-arrested form, but not lacking the acidic domain, caused mitochondrial dysfunction and impaired energy metabolism. These results show, for the first time, that APP is targeted to neuronal mitochondria under some physiological and pathological conditions.

scholarly journals Oral Treponema denticola infection induces Aβ1-40 and Aβ1-42 accumulation in the hippocampus of C57BL/6 mice

2021 ◽  
Author(s):  
Xinyi Su ◽  
Zhiqun Tang ◽  
Yuqiu Liu ◽  
Wanzhi He ◽  
Jiapei Jiang ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Porphyromonas Gingivalis ◽  
Neuronal Cells ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Central Component ◽  
Treponema Denticola ◽  
Periodontal Pathogens ◽  
The Brain

Abstract Accumulation of amyloid-β (Aβ) in the brain is a central component of pathology in Alzheimer’s disease. A growing number of evidences demonstrate close associations between periodontal pathogens including Porphyromonas gingivalis (P. gingivalis) and Treponema denticola (T. denticola) and AD. However, the effect and mechanisms of T. denticola on accumulation of Aβ remain to be unclear. In this study, we demonstrated that T. denticola was able to enter brain and act directly on nerve cells resulting in intra and extracellular Aβ1−40 and Aβ1−42 accumulation in the hippocampus of C57BL/6 mice by selectively activating both β-secretase and γ-secretase. Furthermore, both KMI1303, an inhibitor of β- secretase, as well as DAPT, an inhibitor of γ- secretase were found to be able to inhibit the effect of T. denticola on Aβ accumulation in N2a neuronal cells. Overall, it is concluded that T. denticola increases the expression of Aβ1−42 and Aβ1−40 by its regulation on beta-site amyloid precursor protein cleaving enzyme-1 and Presenilin 1.

scholarly journals Preferred Endocytosis of Amyloid Precursor Protein from Cholesterol-Enriched Lipid Raft Microdomains

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5490
Author(s):  
Yoon Young Cho ◽  
Oh-Hoon Kwon ◽  
Sungkwon Chung
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Cholesterol Levels ◽  
Elevated Cholesterol ◽  
Aβ Generation ◽  
Lipid Raft Microdomains ◽  
First Time

Amyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis and delivered to endo/lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to nonraft-localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results demonstrate for the first time that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimer’s disease.

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 Amyloid-β Peptide Exacerbates the Memory Deficit Caused by Amyloid Precursor Protein Loss-of-Function in Drosophila

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0135741 ◽  
Author(s):  
Isabelle Bourdet ◽  
Aurélie Lampin-Saint-Amaux ◽  
Thomas Preat ◽  
Valérie Goguel
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Memory Deficit ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Loss Of Function ◽  
Protein Loss

scholarly journals Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production

2020 ◽  
Vol 31 (1) ◽  
pp. 27-44 ◽  
Author(s):  
Jing Zhi A. Tan ◽  
Lou Fourriere ◽  
Jingqi Wang ◽  
Franck Perez ◽  
Gaelle Boncompain ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Secretory Pathway ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Primary Neurons ◽  
App Processing

The anterograde trafficking of BACE1 and the potential processing of amyloid precursor protein along the secretory pathway remain poorly defined. Our findings reveal that Golgi exit of BACE1 and APP in primary neurons is tightly regulated, resulting in their segregation along different transport routes, which limits APP processing.

Sign in / Sign up

Export Citation Format

Share Document