Conformational Change in the Ectodomain of the Amyloid Precursor Protein in Response to Proteolytic Processing: The Random Coil Regions Matter

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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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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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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Alzheimer's disease amyloid precursor protein (ApPP): proteolytic processing, secretases and βA4 amyloid production

Amyloid ◽

10.3109/13506129409146118 ◽

1994 ◽

Vol 1 (4) ◽

pp. 263-280 ◽

Cited By ~ 35

Author(s):

Genevieve Evin ◽

Konrad Beyreuther ◽

Colin L. Masters

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Proteolytic Processing ◽

Precursor Protein

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Enhancement of proteolytic processing of the β-amyloid precursor protein by hyperforin

Biochemical Pharmacology ◽

10.1016/j.bcp.2003.08.010 ◽

2003 ◽

Vol 66 (11) ◽

pp. 2177-2184 ◽

Cited By ~ 18

Author(s):

Bettina Froestl ◽

Barbara Steiner ◽

Walter E. Müller

Keyword(s):

Amyloid Precursor Protein ◽

Proteolytic Processing ◽

Precursor Protein ◽

Β Amyloid

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Transcriptional Regulation of BACE1, the β-Amyloid Precursor Protein β-Secretase, by Sp1

Molecular and Cellular Biology ◽

10.1128/mcb.24.2.865-874.2004 ◽

2004 ◽

Vol 24 (2) ◽

pp. 865-874 ◽

Cited By ~ 138

Author(s):

Michelle A. Christensen ◽

Weihui Zhou ◽

Hong Qing ◽

Anna Lehman ◽

Sjaak Philipsen ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Amyloid Precursor Protein ◽

Proteolytic Processing ◽

Precursor Protein ◽

Transcriptional Level ◽

Response Element ◽

App Processing ◽

Transcription Factor Sp1 ◽

Β Amyloid

ABSTRACT Proteolytic processing of the β-amyloid precursor protein (APP) at the β site is essential to generate Aβ. BACE1, the major β-secretase involved in cleaving APP, has been identified as a type 1 membrane-associated aspartyl protease. We have cloned a 2.1-kb fragment upstream of the human BACE1 gene and identified key regions necessary for promoter activity. BACE1 gene expression is controlled by a TATA-less promoter. The region of bp −619 to +46 is the minimal promoter to control the transcription of the BACE1 gene. Several putative cis-acting elements, such as a GC box, HSF-1, a PU box, AP1, AP2, and lymphokine response element, are found in the 5′ flanking region of the BACE1 gene. Transcriptional activation and gel shift assays demonstrated that the BACE1 promoter contains a functional Sp1 response element, and overexpression of the transcription factor Sp1 potentiates BACE gene expression and APP processing to generate Aβ. Furthermore, Sp1 knockout reduced BACE1 expression. These results suggest that BACE1 gene expression is tightly regulated at the transcriptional level and that the transcription factor Sp1 plays an important role in regulation of BACE1 to process APP generating Aβ in Alzheimer's disease.

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