scholarly journals Polarized secretion of beta-amyloid precursor protein and amyloid beta-peptide in MDCK cells.

1994 ◽  
Vol 91 (4) ◽  
pp. 1564-1568 ◽  
Author(s):  
C. Haass ◽  
E. H. Koo ◽  
D. B. Teplow ◽  
D. J. Selkoe
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Mdck Cells ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Amyloid Beta Peptide ◽  
Polarized Secretion ◽  
Beta Peptide

G-lymphatic, vascular and immune pathways for Aβ clearance cascade and therapeutic targets for Alzheimer’s disease

2020 ◽  
Vol 23 ◽  
Author(s):  
Saurav Chakraborty ◽  
Jyothsna ThimmaReddygari ◽  
Divakar Selvaraj
Keyword(s):  
Alzheimer Disease ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Complement System ◽  
Therapeutic Targets ◽  
Neuronal Cell ◽  
Precursor Protein ◽  
Amyloid Beta Peptide ◽  
Beta Peptide ◽  
Immune Pathways

The Alzheimer disease is a age related neurodegenerative disease. The factors causing alzheimer disease are numerous. Research on humans and rodent models predicted various causative factors involved in Alzheimer disease progression. Among them, neuroinflammation, oxidative stress and apoptosis play a major role because of accumulation of extracellular amyloid beta peptides. Here, the clearance of amyloid beta peptide plays a major role because of the imbalance in the production and clearance of the amyloid beta peptide. Additionally, neuroinflammation by microglia, astrocytes, cytokines, chemokines and the complement system also have a major role in Alzheimer disease. The physiological clearance pathways involved in amyloid beta peptide are glymphatic, vascular and immune pathways. Amyloid precursor protein, low density lipoprotein receptor-related protein 1, receptor for advanced glycation end product, apolipoprotein E, clusterin, aquaporin 4, auto-antibodies, complement system, cytokines and microglia are involved in amyloid beta peptide clearance pathways across the blood brain barrier. The plaque formation in the brain by alternative splicing of amyloid precursor protein and production of misfolded protein results in amyloid beta agglomeration. This insoluble amyloid beta leads to neurodegenerative cascade and neuronal cell death occurs. Studies had shown disturbed sleep may be a risk factor for dementia and cognitive decline. In this review, the therapeutic targets for alzheimer disease via focussing on pathways for amyloid beta clearance are discussed.

scholarly journals The orphan drug dichloroacetate reduces amyloid beta-peptide production whilst promoting non-amyloidogenic proteolysis of the amyloid precursor protein

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0255715
Author(s):  
Edward T. Parkin ◽  
Jessica E. Hammond ◽  
Lauren Owens ◽  
Matthew D. Hodges
Keyword(s):  
Amyloid Precursor Protein ◽  
Orphan Drug ◽  
Amyloid Beta ◽  
Precursor Protein ◽  
Amyloid Beta Peptide ◽  
Amyloid Beta Peptides ◽  
Over Expression ◽  
Beta Peptides ◽  
Amyloidogenic Processing ◽  
Beta Peptide

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.

scholarly journals Natural Compounds with Anti-BACE1 Activity as Promising Therapeutic Drugs for Treating Alzheimerʼs Disease

Planta Medica ◽  
2019 ◽  
Vol 85 (17) ◽  
pp. 1316-1325 ◽  
Author(s):  
Mehjabeen Naushad ◽  
Siva Sundara Kumar Durairajan ◽  
Amal Kanti Bera ◽  
Sanjib Senapati ◽  
Min Li
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Neuronal Damage ◽  
Senile Plaques ◽  
Natural Compounds ◽  
Precursor Protein ◽  
Amyloid Beta Peptide ◽  
Primary Concern ◽  
Increased Risk ◽  
Beta Peptide

AbstractAlzheimerʼs disease is a neurodegenerative disease that leads to irreversible neuronal damage. Senile plaques, composed of amyloid beta peptide, is the principal abnormal characteristic of the disease. Among the factors involved, the secretase enzymes, namely, α secretase, beta-site amyloid precursor protein-cleaving enzyme, β secretase, and γ secretase, hold consequential importance. Beta-site amyloid precursor protein-cleaving enzyme 1 is considered to be the rate-limiting factor in the production of amyloid beta peptide. Research supporting the concept of inhibition of beta-site amyloid precursor protein-cleaving enzyme activity as one of the effective therapeutic targets in the mitigation of Alzheimerʼs disease is well accepted. The identification of natural compounds, such as β-amyloid precursor protein-selective beta-site amyloid precursor protein-cleaving enzyme inhibitors, and the idea of compartmentalisation of the beta-site amyloid precursor protein-cleaving enzyme 1 action have caused a dire need to closely examine the natural compounds and their effectiveness in the disease mitigation. Many natural compounds have been reported to effectively modulate beta-site amyloid precursor protein-cleaving enzyme 1. At lower doses, compounds like 2,2′,4′-trihydroxychalcone acid, quercetin, and myricetin have been shown to effectively reduce beta-site amyloid precursor protein-cleaving enzyme 1 activity. The currently used five drugs that are marketed and used for the management of Alzheimerʼs disease have an increased risk of toxicity and restricted therapeutic efficiency, hence, the search for new anti-Alzheimerʼs disease drugs is of primary concern. A variety of natural compounds having pure pharmacological moieties showing multitargeting activity and others exhibiting specific beta-site amyloid precursor protein-cleaving enzyme 1 inhibition as discussed below have superior biosafety. Many of these compounds, which are isolated from medicinal herbs and marine flora, have been long used for the treatment of various ailments since ancient times in the Chinese and Ayurvedic medical systems. The aim of this article is to review the available data on the selected natural compounds, giving emphasis to the inhibition of beta-site amyloid precursor protein-cleaving enzyme 1 activity as a mode of Alzheimerʼs disease treatment.

scholarly journals The orphan drug dichloroacetate reduces amyloid beta-peptide production whilst promoting non-amyloidogenic proteolysis of the amyloid precursor protein

2021 ◽  
Author(s):  
Edward Thomas Parkin ◽  
Jessica E. Hammond ◽  
Matthew D. Hodges
Keyword(s):  
Amyloid Precursor Protein ◽  
Orphan Drug ◽  
Amyloid Beta ◽  
Precursor Protein ◽  
Amyloid Beta Peptide ◽  
Amyloid Beta Peptides ◽  
Over Expression ◽  
Beta Peptides ◽  
Amyloidogenic Processing ◽  
Beta Peptide

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 of α-, β- or γ-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. As the drug is already used for the treatment of lactic acidosis and is known to cross the blood-brain-barrier, it might represent a cheap and effective therapy for slowing the progression of Alzheimer’s disease.

Aβ42 oligomers impair the bioenergetic activity in hippocampal synaptosomes derived from APP-KO mice

2018 ◽  
Vol 399 (5) ◽  
pp. 453-465
Author(s):  
Benedikt Beckert ◽  
Amparo Acker-Palmer ◽  
Walter Volknandt
Keyword(s):  
Amyloid Precursor Protein ◽  
Mitochondrial Membrane ◽  
Molecular Mechanisms ◽  
Model System ◽  
Precursor Protein ◽  
Amyloid Beta Peptide ◽  
Mitochondrial Activity ◽  
Suitable Model ◽  
Beta Peptide ◽  
The Impact

Abstract Employing hippocampal synaptosomes from amyloid precursor protein (APP)-deleted mice we analyzed the immediate effects of amyloid beta peptide 42 (Aβ42) peptide in its oligomeric or fibrillar assembly or of soluble amyloid precursor protein alpha (sAPPα) protein on their bioenergetic activity. Upon administration of oligomeric Aβ42 peptide for 30 min we observed a robust decrease both in mitochondrial activity and in mitochondrial membrane potential (MMP). In contrast the respective fibrillary or scrambled peptides showed no effect, indicating that inhibition strictly depends on the oligomerization status of the peptide. Hippocampal synaptosomes from old APP-KO mice revealed a further reduction of their already impaired bioenergetic activity upon incubation with 10 μm Aβ42 peptide. In addition we evaluated the influence of the sAPPα protein on mitochondrial activity of hippocampal synaptosomes derived from young or old APP-KO animals. In neither case 20 nm nor 200 nm sAPPα protein had an effect on mitochondrial metabolic activity. Our findings demonstrate that hippocampal synaptosomes derived from APP-KO mice are a most suitable model system to evaluate the impact of Aβ42 peptide on its bioenergetic activity and to further elucidate the molecular mechanisms underlying the impairments by oligomeric Aβ42 on mitochondrial function. Our data demonstrate that extracellular Aβ42 peptide is taken up into synaptosomes where it immediately attenuates mitochondrial activity.

scholarly journals Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons.

1995 ◽  
Vol 129 (2) ◽  
pp. 431-442 ◽  
Author(s):  
T Yamazaki ◽  
D J Selkoe ◽  
E H Koo
Keyword(s):  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Hippocampal Neurons ◽  
Mdck Cells ◽  
Sympathetic Neurons ◽  
Senile Plaques ◽  
Indirect Evidence ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Cultured Neurons

Amyloid beta-protein (A beta), the principal constituent of senile plaques seen in Alzheimer's disease (AD), is derived by proteolysis from the beta-amyloid precursor protein (beta PP). The mechanism of A beta production in neurons, which are hypothesized to be a rich source of A beta in brain, remains to be defined. In this study, we describe a detailed localization of cell surface beta PP and its subsequent trafficking in primary cultured neurons. Full-length cell surface beta PP was present primarily on perikarya and axons, the latter with a characteristic discontinuous pattern. At growth cones, cell surface beta PP was inconsistently detected. By visualizing the distribution of beta PP monoclonal antibodies added to intact cultures, beta PP was shown to be internalized from distal axons or terminals and retrogradely transported back to perikarya in organelles which colocalized with fluid-phase endocytic markers. Retrograde transport of beta PP was shown in both hippocampal and peripheral sympathetic neurons, the latter using a compartment culture system that isolated cell bodies from distal axons and terminals. In addition, we demonstrated that beta PP from distal axons was transcytotically transported to the surface of perikarya from distal axons in sympathetic neurons. Indirect evidence of this transcytotic pathway was obtained in hippocampal neurons using antisense oligonucleotide to the kinesin heavy chain to inhibit anterograde beta PP transport. Taken together, these results demonstrate novel aspects of beta PP trafficking in neurons, including retrograde axonal transport and transcytosis. Moreover, the axonal predominance of cell surface beta PP is unexpected in view of the recent report of polarized sorting of beta PP to the basolateral domain of MDCK cells.

Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody

1996 ◽  
Vol 109 (5) ◽  
pp. 991-998 ◽  
Author(s):  
E.H. Koo ◽  
S.L. Squazzo ◽  
D.J. Selkoe ◽  
C.H. Koo
Keyword(s):  
Monoclonal Antibody ◽  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Senile Plaques ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Secretory Product ◽  
Amyloid Beta Protein ◽  
Lysosomal Compartment

Amyloid beta-protein, the principal constituent of amyloid fibrils found in senile plaques and blood vessels in Alzheimer's disease, is constitutively produced and released into medium of cultured cells. Amyloid beta-protein is derived by proteolysis of the beta-amyloid precursor protein by unclear mechanisms. Beta-amyloid precursor protein is a transmembrane protein which can be processed to release a large secretory product or processed in the endosomal/lysosomal pathway without secretion. Previous studies have shown that from the cell surface, beta-amyloid precursor protein may be released after cleavage or internalized without cleavage, the latter in a pathway that both produces amyloid beta-protein and also targets some molecules to the lysosomal compartment. Analysis of beta-amyloid precursor protein trafficking is confounded by the concomitant secretion and internalization of molecules from the cell surface. To address this issue, we developed an assay, based on the binding of radioiodinated monoclonal antibody, to measure the release and internalization of cell surface beta-amyloid precursor protein in transfected cells. With this approach, we showed that surface beta-amyloid precursor protein is either rapidly released or internalized, such that the duration at the cell surface is very short. Approximately 30% of cell surface beta-amyloid precursor protein molecules are released. Following internalization, a fraction of molecules are recycled while the majority of molecules are rapidly sorted to the lysosomal compartment for degradation When the C terminus of beta-amyloid precursor protein is deleted, secretion is increased by approximately 2.5-fold as compared to wild-type molecules. There is concomitant decrease in internalization in these mutant molecules as well as prolongation of the resident time on the cell surface. This observation is consistent with recent evidence that signals within the cytoplasmic domain mediate beta-amyloid precursor protein internalization.

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