Proteolytic processing and cell biological functions of the amyloid precursor protein

Recent research has identified some key players involved in the proteolytic processing of amyloid precursor protein (APP) to amyloid beta-peptide, the principal component of the amyloid plaques in Alzheimer patients. Interesting parallels exists with the proteolysis of other proteins involved in cell differentiation, cholesterol homeostasis and stress responses. Since the cytoplasmic domain of APP is anchored to a complex protein network that might function in axonal elongation, dendritic arborisation and neuronal cell migration, the proteolysis of APP might be critically involved in intracellular signalling events.

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

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207323666200901095003 ◽

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.

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Tetrahydrohyperforin Inhibits the Proteolytic Processing of Amyloid Precursor Protein and Enhances Its Degradation by Atg5-Dependent Autophagy

PLoS ONE ◽

10.1371/journal.pone.0136313 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0136313 ◽

Cited By ~ 15

Author(s):

Viviana A. Cavieres ◽

Alexis González ◽

Vanessa C. Muñoz ◽

Claudia P. Yefi ◽

Hianara A. Bustamante ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Proteolytic Processing ◽

Precursor Protein

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

PLoS ONE ◽

10.1371/journal.pone.0255715 ◽

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.

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Involvement of c-Jun N-terminal kinase in amyloid precursor protein-mediated neuronal cell death

Journal of Neurochemistry ◽

10.1046/j.1471-4159.2003.01585.x ◽

2003 ◽

Vol 84 (4) ◽

pp. 864-877 ◽

Cited By ~ 68

Author(s):

Yuichi Hashimoto ◽

Osahiko Tsuji ◽

Takako Niikura ◽

Yohichi Yamagishi ◽

Miho Ishizaka ◽

...

Keyword(s):

Cell Death ◽

Amyloid Precursor Protein ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Precursor Protein

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Amyloid Precursor Protein (APP) and GABAergic Neurotransmission

Cells ◽

10.3390/cells8060550 ◽

2019 ◽

Vol 8 (6) ◽

pp. 550 ◽

Cited By ~ 9

Author(s):

Bor Luen Tang

Keyword(s):

Amyloid Precursor Protein ◽

Gabab Receptor ◽

Reversal Potential ◽

Proteolytic Processing ◽

Precursor Protein ◽

Mammalian Brain ◽

Gabaergic Neurotransmission ◽

Physiological Importance ◽

Presynaptic Plasma Membrane ◽

Etiological Agents

The amyloid precursor protein (APP) is the parent polypeptide from which amyloid-beta (Aβ) peptides, key etiological agents of Alzheimer’s disease (AD), are generated by sequential proteolytic processing involving β- and γ-secretases. APP mutations underlie familial, early-onset AD, and the involvement of APP in AD pathology has been extensively studied. However, APP has important physiological roles in the mammalian brain, particularly its modulation of synaptic functions and neuronal survival. Recent works have now shown that APP could directly modulate γ-aminobutyric acid (GABA) neurotransmission in two broad ways. Firstly, APP is shown to interact with and modulate the levels and activity of the neuron-specific Potassium-Chloride (K+-Cl−) cotransporter KCC2/SLC12A5. The latter is key to the maintenance of neuronal chloride (Cl−) levels and the GABA reversal potential (EGABA), and is therefore important for postsynaptic GABAergic inhibition through the ionotropic GABAA receptors. Secondly, APP binds to the sushi domain of metabotropic GABAB receptor 1a (GABABR1a). In this regard, APP complexes and is co-transported with GABAB receptor dimers bearing GABABR1a to the axonal presynaptic plasma membrane. On the other hand, secreted (s)APP generated by secretase cleavages could act as a GABABR1a-binding ligand that modulates presynaptic vesicle release. The discovery of these novel roles and activities of APP in GABAergic neurotransmission underlies the physiological importance of APP in postnatal brain function.

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The Amyloid Precursor Protein Represses Expression of Acetylcholinesterase in Neuronal Cell Lines

Journal of Biological Chemistry ◽

10.1074/jbc.m113.461269 ◽

2013 ◽

Vol 288 (36) ◽

pp. 26039-26051 ◽

Cited By ~ 10

Author(s):

David A. Hicks ◽

Natalia Z. Makova ◽

Mallory Gough ◽

Edward T. Parkin ◽

Natalia N. Nalivaeva ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Cell Lines ◽

Neuronal Cell ◽

Precursor Protein ◽

Neuronal Cell Lines

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Adaptor protein 2–mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing

Molecular Biology of the Cell ◽

10.1091/mbc.e11-11-0944 ◽

2012 ◽

Vol 23 (12) ◽

pp. 2339-2351 ◽

Cited By ~ 46

Author(s):

Yogikala Prabhu ◽

Patricia V. Burgos ◽

Christina Schindler ◽

Ginny G. Farías ◽

Javier G. Magadán ◽

...

Keyword(s):

Plasma Membrane ◽

Amyloid Precursor Protein ◽

Secretory Pathway ◽

Brefeldin A ◽

Adaptor Protein ◽

Proteolytic Processing ◽

Precursor Protein ◽

Amyloid Precursor Protein Processing ◽

Intermediate Compartment ◽

Golgi Network

The β-site amyloid precursor protein (APP)–cleaving enzyme 1 (BACE1) is a transmembrane aspartyl protease that catalyzes the proteolytic processing of APP and other plasma membrane protein precursors. BACE1 cycles between the trans-Golgi network (TGN), the plasma membrane, and endosomes by virtue of signals contained within its cytosolic C-terminal domain. One of these signals is the DXXLL-motif sequence DISLL, which controls transport between the TGN and endosomes via interaction with GGA proteins. Here we show that the DISLL sequence is embedded within a longer [DE]XXXL[LI]-motif sequence, DDISLL, which mediates internalization from the plasma membrane by interaction with the clathrin-associated, heterotetrameric adaptor protein 2 (AP-2) complex. Mutation of this signal or knockdown of either AP-2 or clathrin decreases endosomal localization and increases plasma membrane localization of BACE1. Remarkably, internalization-defective BACE1 is able to cleave an APP mutant that itself cannot be delivered to endosomes. The drug brefeldin A reversibly prevents BACE1-catalyzed APP cleavage, ruling out that this reaction occurs in the endoplasmic reticulum (ER) or ER–Golgi intermediate compartment. Taken together, these observations support the notion that BACE1 is capable of cleaving APP in late compartments of the secretory pathway.

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