Structure and functions of the human amyloid precursor protein: The whole is more than the sum of its parts

Gralle, Matthias; Ferreira, Sérgio T.

doi:10.1016/j.pneurobio.2007.02.001

Cited by 161 publications

(130 citation statements)

References 218 publications

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“…Using the same model, central and peripheral administration of an antisense oligonucleotide targeting APP, reduced formation of Aβ, and improved the AD phenotype (Farr et al, 2014). However, APP has multiple morphoregulatory functions, like regulation of neurite outgrowth, and complete knockdown of APP expression could lead to major side effects (Gralle and Ferreira, 2007). Also, the formation of the toxic Aβ peptides from APP could be prevented by increasing α-secretase activity or inhibiting the β-or γ-secretase activity.…”

Section: Potential Therapies For Hchwa-dmentioning

confidence: 99%

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Kamp

Moursel²,

Haan³

et al. 2014

Reviews in the Neurosciences

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Hereditary cerebral hemorrhage with amyloidosis – Dutch type is an autosomal dominant hereditary disease caused by a point mutation in the amyloid precursor protein gene on chromosome 21. The mutation causes an amino acid substitution at codon 693 (E22Q), the ‘Dutch mutation’. Amyloid β, the product after cleavage of the amyloid precursor protein, is secreted into the extracellular space. The Dutch mutation leads to altered amyloid β cleavage and secretion, enhanced aggregation properties, higher proteolysis resistance, lowered brain efflux transporter affinity, and enhanced cell surfaces binding. All these result in amyloid β accumulation in cerebral vessel walls, causing cell death and vessel wall integrity loss, making cerebral vessel walls in hereditary cerebral hemorrhage with amyloidosis-Dutch type more prone to rupture and obstruction, leading to hemorrhages and infarcts. Studying the effects of altered amyloid β metabolism due to mutations like the ‘Dutch’ provides us with a better understanding of amyloid β toxicity, also in other amyloid β diseases like sporadic cerebral amyloid angiopathy and Alzheimer’s disease.

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Section: Potential Therapies For Hchwa-dmentioning

confidence: 99%

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Kamp

Moursel²,

Haan³

et al. 2014

Reviews in the Neurosciences

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“…This inhibitory activity has been localized to the Kunitz domain of sAPP (25). Subsequently, sAPP has been found to stimulate growth in both neuronal and epithelial cells, to influence neurite outgrowth and synaptogenesis in the nervous system, and to stimulate motility in epithelial cells (26,27). As an intact integral membrane protein, the structure of APP suggests similarity to membrane receptors (28), and recent data have suggested possible roles for APP as a cell surface receptor with signaling functions activated through cell-cell and cellextracellular matrix contacts (26) and through proteolysis (29).…”

mentioning

confidence: 99%

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Salameh

Robinson

Navaneetham

et al. 2010

Journal of Biological Chemistry

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The amyloid precursor protein (APP) is a ubiquitously expressed transmembrane adhesion protein and the progenitor of amyloid-␤ peptides. The major splice isoforms of APP expressed by most tissues contain a Kunitz protease inhibitor domain; secreted APP containing this domain is also known as protease nexin 2 and potently inhibits serine proteases, including trypsin and coagulation factors. The atypical human trypsin isoform mesotrypsin is resistant to inhibition by most protein protease inhibitors and cleaves some inhibitors at a substantially accelerated rate. Here, in a proteomic screen to identify potential physiological substrates of mesotrypsin, we find that APP/protease nexin 2 is selectively cleaved by mesotrypsin within the Kunitz protease inhibitor domain. In studies employing the recombinant Kunitz domain of APP (APPI), we show that mesotrypsin cleaves selectively at the Arg 15 -Ala 16 reactive site bond, with kinetic constants approaching those of other proteases toward highly specific protein substrates. Finally, we show that cleavage of APPI compromises its inhibition of other serine proteases, including cationic trypsin and factor XIa, by 2 orders of magnitude. Because APP/protease nexin 2 and mesotrypsin are coexpressed in a number of tissues, we suggest that processing by mesotrypsin may ablate the protease inhibitory function of APP/protease nexin 2 in vivo and may also modulate other activities of APP/protease nexin 2 that involve the Kunitz domain.Mesotrypsin is a human trypsin encoded by the PRSS3 gene found on chromosome 9p13 (1). Normal expression of PRSS3 is restricted to pancreas, brain, and, to a lesser extent, small intestine and colon (2-4); additionally, PRSS3 appears to be transcriptionally up-regulated with cancer progression in epithelial cancers, including lung (5), colon (6), and prostate. Mesotrypsin exhibits substantially different specificity from other trypsins toward protein substrates. It fails to activate pancreatic zymogens and also shows reduced capacity to degrade trypsinogens (7). Compared with other trypsins, it is significantly compromised in its ability to cleave protease-activated receptors (8 -10). Despite limited activity toward these classic trypsin substrates, mesotrypsin displays enhanced catalytic activity compared with other trypsins in the cleavage of certain specific protein substrates, most notably several canonical protease inhibitors (7, 11).The "canonical" inhibitors of serine proteases, named for a protease-binding loop of highly characteristic backbone conformation (12, 13), fulfill the paradoxical function of binding to a protease in a substrate-like manner yet acting as an inhibitor rather than an ordinary substrate. These inhibitors, representing at least 18 different convergently evolved protein families (14, 15), inhibit their cognate proteases via the "Laskowski mechanism," in which inhibitors act as highly specific, limited proteolysis substrates for target enzymes (14, 16). They bind so as to position a specific peptide bond, the "reactive si...

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“…These fibrils are formed of Aβ derived from the proteolytic cleavage of the amyloid precursor protein (APP) [57], however soluble Aβ oligomers (AβOs), which are not detected through regular tissue staining techniques, have been demonstrated to be the neurotoxic form of Aβ [29,58].…”

Section: Discussionmentioning

confidence: 99%

Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMAIII) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression

et al. 2016

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Long-term exposure to inorganic arsenic (iAs) through drinking water has been associated with cognitive impairment in children and adults; however, the related pathogenic mechanisms have not been completely described. Increased or chronic inflammation in the brain is linked to impaired cognition and neurodegeneration; iAs induces strong inflammatory responses in several cells, but this effect has been poorly evaluated in central nervous system (CNS) cells.Because astrocytes are the most abundant cells in the CNS and play a critical role in brain homeostasis, including regulation of the inflammatory response, any functional impairment in them can be deleterious for the brain. We propose that iAs could induce cognitive impairment through inflammatory response activation in astrocytes. In the present work, rat cortical astrocytes were acutely exposed in vitro to the monomethylated metabolite of iAs (MMA III ), which accumulates in glial cells without compromising cell viability. MMA III LD 50 in astrocytes was 10.52 μM, however, exposure to sub-toxic MMA III concentrations (50 to 1000 nM) significantly increased IL-1β, IL-6, TNF-α, COX-2, and MIF-1 gene expression. These effects were consistent with amyloid precursor protein (APP) and β-secretase (BACE-1) increased gene expression, mainly for those MMA III concentrations that also induced TNF-α over-expression. Other effects of MMA III on cortical astrocytes included increased proliferative and metabolic activity. All tested MMA III concentrations led to an inhibition of intracellular lactate dehydrogenase (LDH) activity. Results suggest that MMA III induces important metabolic and functional changes in astrocytes that may affect brain homeostasis and that inflammation may play a major role in cognitive impairment-related pathogenicity in As-exposed populations.

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Structure and functions of the human amyloid precursor protein: The whole is more than the sum of its parts

Cited by 161 publications

References 218 publications

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Cortical Astrocytes Acutely Exposed to the Monomethylarsonous Acid (MMAIII) Show Increased Pro-inflammatory Cytokines Gene Expression that is Consistent with APP and BACE-1: Over-expression

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