Noradrenergic Sympathetic Sprouting and Cholinergic Reinnervation Maintains Non-Amyloidogenic Processing of AβPP

The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimer’s disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by β- and γ-secretases in the ’amyloidogenic’ proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the ’non-amyloidogenic’ pathway which, through the action of the α-secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPPα. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPPα generation whilst inhibiting β–secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the β-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression/activity of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. Given the small size and blood-brain-barrier permeability of the drug, further research into its mechanism of action with respect to APP proteolysis may lead to the development of therapies for slowing the progression of Alzheimer’s disease.

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Importance and prospects for design of selective muscarinic agonists

Physiological Research ◽

10.33549/physiolres.931449 ◽

2008 ◽

pp. S39-S47

Author(s):

J Jakubík ◽

P Michal ◽

E Machová ◽

V Doležal

Keyword(s):

Binding Sites ◽

Natural Aging ◽

Receptor Activation ◽

Receptor Subtypes ◽

Muscarinic Agonists ◽

Amyloidogenic Processing ◽

M1 Receptor ◽

The Central Nervous System ◽

M1 Agonist ◽

Stimulation Of

There are five subtypes of muscarinic receptors that serve various important physiological functions in the central nervous system and the periphery. Mental functions like attention, learning, and memory are attributed to the muscarinic M1 subtype. These functions decline during natural aging and an early deficit is typical for Alzheimer s disease. In addition, stimulation of the M1 receptor increases non-amyloidogenic processing of the amyloid precursor protein and thus prevents accumulation of noxious beta-amyloid fragments. The selectivity of classical muscarinic agonists among receptor subtypes is very low due to the highly conserved nature of the orthosteric binding site among receptor subtypes. Herein we summarize some recent studies with the functionally-selective M1 agonist xanomeline that indicate complex pharmacological profile of this drug that includes interactions with and activation of receptor from both orthosteric and ectopic binding sites, and the time-dependent changes of ligand binding and receptor activation. These findings point to potential profitability of exploitation of ectopic ligands in the search for truly selective muscarinic receptor agonists.

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Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes

Journal of Cell Science ◽

10.1242/jcs.214536 ◽

2018 ◽

Vol 131 (11) ◽

pp. jcs214536 ◽

Cited By ~ 4

Author(s):

María Gabriela Otero ◽

Ivan Fernandez Bessone ◽

Alan Earle Hallberg ◽

Lucas Eneas Cromberg ◽

María Cecilia De Rossi ◽

...

Keyword(s):

Axonal Transport ◽

Amyloidogenic Processing

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Sympathetic Sprouting in Rat Thoracolumbar Dorsal Root Ganglia During Colitis

Gastroenterology ◽

10.1016/s0016-5085(11)62227-0 ◽

2011 ◽

Vol 140 (5) ◽

pp. S-537

Author(s):

Chun-Mei Xia ◽

Denis G. Colomb ◽

Hamid I. Akbarali ◽

Li-Ya Qiao

Keyword(s):

Dorsal Root Ganglia ◽

Dorsal Root ◽

Sympathetic Sprouting

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Effects of Mild and Severe Oxidative Stress on BACE1 Expression and APP Amyloidogenic Processing

Systems Biology of Alzheimer's Disease - Methods in Molecular Biology ◽

10.1007/978-1-4939-2627-5_4 ◽

2016 ◽

pp. 101-116 ◽

Cited By ~ 9

Author(s):

Jiangli Tan ◽

Qiao-Xin Li ◽

Genevieve Evin

Keyword(s):

Oxidative Stress ◽

Amyloidogenic Processing ◽

Bace1 Expression

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Abstract W P359: Activation of Prostacyclin Receptor (IP) in Human Brain Microvascular Endothelial Cells Stimulates Production of SAPPa

Stroke ◽

10.1161/str.45.suppl_1.wp359 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Tongrong He ◽

Tong Lu ◽

Zvinomir Katusic

Keyword(s):

Endothelial Cells ◽

Protein Expression ◽

Human Brain ◽

Microvascular Endothelial Cells ◽

Mrna Levels ◽

Brain Microvascular Endothelial Cells ◽

Camp Pathway ◽

Processing Enzyme ◽

Amyloidogenic Processing ◽

Adam10 Expression

Previous studies have established that cerebral blood vessels possess high capacity to synthesize prostacyclin (PGI 2 ). Substantial evidence indicates that amyloid precursor protein (APP) and soluble APPα (sAPPα) have neurotrophic and nueroprotective properties. We hypothesized that activation of IP-cAMP pathway stimulates non-amyloidogenic processing of APP in cerebral endothelial cells. Western blotting was used to detect protein expression; real time RT-PCR was employed to measure mRNA levels of APP, and a disintegrin and metalloprotease 10 (ADAM10, an α processing enzyme); sAPPα secretion was detected in condition medium derived from culturing human brain microvascular endothelial cells (BMVECs), by ELISA. After human BMVECs were treated with PGI 2 analog iloprost (0.01, 0.05, 0.1, or 0.5 μM) for 3 days, protein levels of ADAM10 (n=7-9, P<0.05) and APP (n=6, P<0.05) were significantly increased in a concentration dependent manner, while β amyloidogenic processing enzyme BACE1, and other α processing enzymes such as ADAM9 and ADAM17 were not changed. mRNA levels of APP (n=7, P<0.05) and ADAM10 (n=4, P<0.05), as well as sAPPα production in human BMVECs (n=6, P<0.05) were also significantly augmented in response to iloprost treatment. Moreover, stimulation of human BMVECs with forskolin (40μM) significantly enhanced APP and ADAM10 protein expression. Most notably, iloprost significantly augmented protein expression of peroxisome proliferation-activated receptor-δ (PPARδ) and SIRT1. We further explored the role of PPARδ in APP processing. ADAM10 expression (n=6, P<0.05), but not APP and BACE1, was significantly increased in human BMVECs treated with PPARδ ligand GW501516 (30 or 100 nM). GW501516 (100 nM) also significantly increase sAPPα production (n=9-10, P<0.05). siRNA against PPARδ significantly suppressed basal levels of ADAM10, and blocked iloprost-induced ADAM10 expression (n=4, P<0.05). These findings suggest that activation of IP-cAMP pathway enhances non-amyloidogenic processing of APP and consequently increases production of neurotrophic molecule sAPPα in human BMVECs. Activation of PPARδ in part mediates iloprost-induced α processing of APP.

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