scholarly journals Impact of putative cilia targeting sequences on APP trafficking

2020 ◽  
Vol 16 (S2) ◽  
Author(s):  
Swathi Swaminathan
Keyword(s):  
App Trafficking

scholarly journals MT5-MMP Promotes Alzheimer’s Pathogenesis in the Frontal Cortex of 5xFAD Mice and APP Trafficking in vitro

2017 ◽  
Vol 9 ◽  
Author(s):  
Kévin Baranger ◽  
Amandine E. Bonnet ◽  
Stéphane D. Girard ◽  
Jean-Michel Paumier ◽  
Laura García-González ◽  
...  
Keyword(s):  
Frontal Cortex ◽  
App Trafficking ◽  
5Xfad Mice

scholarly journals Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-β in Human Skin Fibroblasts from Familial Alzheimer’s Disease

2020 ◽  
Vol 10 (4) ◽  
pp. 232
Author(s):  
Antaripa Bhattacharya ◽  
Antonella Izzo ◽  
Nunzia Mollo ◽  
Filomena Napolitano ◽  
Adriana Limone ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Golgi Apparatus ◽  
Protein Misfolding ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Laminin Receptor ◽  
Mitochondrial Network ◽  
App Trafficking ◽  
Healthy Control

Alzheimer’s disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aβ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, Aβ and 37/67kDa laminin receptor (LR), finding the possibility to regulate intracellular APP localization and maturation through modulation of the receptor. Here, we report that in fibroblasts from familial AD (fAD), APP was prevalently expressed as an immature isoform and accumulated preferentially in the transferrin-positive recycling compartment rather than in the Golgi apparatus. Moreover, besides the altered mitochondrial network exhibited by fAD patient cells, the levels of pAkt and pGSK3 were reduced in respect to healthy control fibroblasts and were accompanied by an increased amount of secreted Aβ in conditioned medium from cell cultures. Interestingly, these features were reversed by inhibition of 37/67kDa LR by NSC47924 a small molecule that was able to rescue the “typical” APP localization in the Golgi apparatus, with consequences on the Aβ level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and Aβ levels with implications in Alzheimer’s disease.

Oxidative Stress Targeting Amyloid Beta Accumulation and Clearance in Alzheimer’s Disease: Insight into Pathological Mechanisms and Therapeutic Strategies

2020 ◽  
Vol 9 (1) ◽  
pp. 22-42
Author(s):  
Sunpreet Kaur ◽  
Puneet Kumar ◽  
Shamsher Singh
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Neurodegenerative Disorder ◽  
Acetylcholinesterase Inhibitors ◽  
The Elderly ◽  
Biochemical Alterations ◽  
App Trafficking ◽  
Copper Aluminum

Background: Alzheimer’s disease is the most common neurodegenerative disorder affecting the elderly population and emerges as a leading challenge for the scientific research community. The wide pathological aspects of AD made it a multifactorial disorder and even after long time it’s difficult to treat due to unexplored etiological factors. Methods: The etiogenesis of AD includes mitochondrial failure, gut dysbiosis, biochemical alterations but deposition of amyloid-beta plaques and neurofibrillary tangles are implicated as major hallmarks of neurodegeneration in AD. The aggregates of these proteins disrupt neuronal signaling, enhance oxidative stress and reduce activity of various cellular enzymes which lead to neurodegeneration in the cerebral cortex, neocortex and hippocampus. The metals like copper, aluminum are involved in APP trafficking and promote amyloidbeta aggregation. Similarly, disturbed ubiquitin proteasomal system, autophagy and amyloid- beta clearance mechanisms exert toxic insult in the brain. Result and conclusion : The current review explored the role of oxidative stress in disruption of amyloid homeostasis which further leads to amyloid-beta plaque formation and subsequent neurodegeneration in AD. Presently, management of AD relies on the use of acetylcholinesterase inhibitors, antioxidants and metal chelators but they are not specific measures. Therefore, in this review, we have widely cited the various pathological mechanisms of AD as well as possible therapeutic targets.

scholarly journals Dual role of cofilin in APP trafficking and amyloid-β clearance

2019 ◽  
Vol 33 (12) ◽  
pp. 14234-14247 ◽  
Author(s):  
Tian Liu ◽  
Jung-A. A. Woo ◽  
Yan Yan ◽  
Patrick LePochat ◽  
Mohammed Zaheen Bukhari ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Dual Role ◽  
App Trafficking

scholarly journals LDLR-related protein 10 (LRP10) regulates amyloid precursor protein (APP) trafficking and processing: evidence for a role in Alzheimer’s disease

2012 ◽  
Vol 7 (1) ◽  
pp. 31 ◽  
Author(s):  
Julie Brodeur ◽  
Caroline Thériault ◽  
Mélissa Lessard-Beaudoin ◽  
Alexandre Marcil ◽  
Sophie Dahan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Related Protein ◽  
App Trafficking

LGI3 interacts with flotillin-1 to mediate APP trafficking and exosome formation

Neuroreport ◽  
2010 ◽  
Vol 21 (9) ◽  
pp. 606-610 ◽  
Author(s):  
Sachi Okabayashi ◽  
Nobuyuki Kimura
Keyword(s):  
App Trafficking

scholarly journals Reciprocal Modulation Between Amyloid Precursor Protein and Synaptic Membrane Cholesterol Revealed By Live Cell Imaging

2018 ◽  
Author(s):  
Claire E. DelBove ◽  
Claire E. Strothman ◽  
Roman M. Lazarenko ◽  
Hui Huang ◽  
Charles R. Sanders ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Fluorescent Protein ◽  
Dominant Negative ◽  
Precursor Protein ◽  
Membrane Cholesterol ◽  
Synaptic Membrane ◽  
Surface Distribution ◽  
Cholesterol Levels ◽  
App Trafficking ◽  
Green Fluorescent

SummaryThe amyloid precursor protein (APP) has been extensively studied because of its association with Alzheimer’s disease (AD). However, APP distribution across different subcellular membrane compartments and its function in neurons remains unclear. We generated an APP fusion protein with a pH-sensitive green fluorescent protein at its ectodomain and a pH-insensitive blue fluorescent protein at its cytosolic domain and used it to measure APP’s distribution, subcellular trafficking and cleavage in live neurons. This reporter, closely resembling endogenous APP, revealed only a limited correlation between synaptic activities and APP trafficking. However, the synaptic surface distribution of APP was inversely correlated to membrane cholesterol levels, a phenomenon that involves APP’s cholesterol-binding site. Mutations within this site not only altered surface APP and cholesterol levels in a dominant negative manner, but also increased synaptic vulnerability to moderate membrane cholesterol reduction. Our results reveal reciprocal modulation of APP and membrane cholesterol levels at synaptic boutons.

scholarly journals GSAP Regulates Amyloid Beta Production through Modulation of Amyloid Precursor Protein Trafficking

2020 ◽  
Author(s):  
Jerry C. Chang ◽  
Peng Xu ◽  
Eitan Wong ◽  
Marc Flajolet ◽  
Yue-Ming Li ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
High Speed ◽  
Precursor Protein ◽  
Membrane Microdomains ◽  
Gamma Secretase ◽  
High Association ◽  
Amyloidogenic Processing ◽  
Secretase Activity ◽  
App Trafficking ◽  
Β Amyloid

AbstractIn addition to participating in γ-secretase activity, presenilin 1 (PS1) regulates trafficking and subcellular localization of β-amyloid precursor protein (APP). We previously showed that gamma-secretase activating protein (GSAP) selectively modulates γ-secretase activity by inducing conformational change in PS1. However, little is known whether and how GSAP might influence APP trafficking and consequent generation of β-amyloid (Aβ) peptides. Here, to explore whether GSAP has any role in regulating APP trafficking, and to systematically investigate the intracellular trafficking routes of APP, we paired total internal reflection fluorescence microscopy, high-speed line scanning microscopy, and 4D microscopy with comprehensive imaging analysis methodologies to depict the elusive modes of APP trafficking at a single-vesicle level. Mobility and diffusivity changes reveal the existence of two kinetically distinct pathways, classified into mobile and immobile pools, for vesicular APP trafficking, suggesting high association between immobile vesicle pool and amyloidogenic processing. GSAP knockdown significantly lowers immobile pool without overturning APP vesicle diffusivity, suggesting that GSAP affects vesicular APP trafficking by retaining APP in membrane microdomains known to favor amyloidogenic processing. Our study reveals a novel role of GSAP in the regulation of Aβ-peptide formation that modulates switching of APP vesicles between immobile and mobile pools, which may help identifying new therapeutic strategies to treat Alzheimer’s disease.

scholarly journals GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

2020 ◽  
Author(s):  
Peng Xu ◽  
Jerry C. Chang ◽  
Xiaopu Zhou ◽  
Wei Wang ◽  
Michael Bamkole ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Function ◽  
Protein A ◽  
Transcript Level ◽  
Rna Seq ◽  
Single Nucleotide ◽  
Amyloidogenic Processing ◽  
App Trafficking ◽  
Lipid Environment

ABSTRACTBiochemical, pathogenic and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer’s disease (AD) and Down syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNA-seq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with Fe65:APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization, and lowering GSAP expression reduces pathological effects associated with AD.

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