Tp link tl wn722n. Surya Pandey, Taro Kawai, in, 2014 Amyloid Fibril-Mediated Uptake of DNAAmyloid precursor proteins can form amyloid fibrils in the presence of nucleic acids 103. Recently, it was demonstrated that DNA-containing amyloid fibrils can induce high levels of IFN-α/β production by pDCs in response to self-DNA.
These self-DNA-containing amyloid fibrils are internalized by pDCs and retained in early endosomes to activate TLR9 and produce large amounts of type I IFN. However, the involvement of specific pDC surface receptors, if any, in mediating this internalization is unknown. In vivo as well, DNA-containing amyloid fibrils induced infiltration and activation of pDCs correlating with rapid transcription of type I IFN genes in mice. Furthermore, immunization with DNA-containing amyloid fibrils induced autoantibodies and proteinuria in non-immune mice, thereby establishing an inducible murine model for lupus 104.
Marr, in, 2016 AbstractThe amyloid beta precursor protein more commonly known as the amyloid precursor protein, or APP, is a complex polypeptide playing a part in a diverse array of cellular functions. As implied by its name, most of the initial and much of the continued interest in APP arises from its connection to Alzheimer’s disease (AD) and its role in the generation of the amyloid-beta peptide. However, it has become clear that this protein and its many proteolytic products are also important for the proper function of the nervous system and could be linked to AD in multiple ways.
In order to understand the roles APP may play in AD, this chapter will first describe the characteristics of APP and its associated cellular pathways/functions before addressing the ways in which APP function or dysfunction can contribute to AD. Nicholls, Stuart J. Ferguson, in, 2013 188.8.131.52 β-Amyloid effects on mitochondriaFurther reading: Du et al.
(2010), Eckert et al. (2011), Pagani and Eckert (2011)Amyloid precursor protein (APP) is an integral glycoprotein ubiquitously expressed in the plasma membrane; its normal function is unclear.
As with other integral plasma membrane proteins, APP is synthesised in the endoplasmic reticulum, trafficked through the Golgi to the cell surface, and undergoes endosomal retrieval. APP can be cleaved by three secretases—α, β and γ.
Sequential cleavage by β- and γ-secretases liberates β-amyloid peptides of varying length, particularly Aβ 40 and Aβ 42. The catalytic subunit of γ-secretase is the aspartyl protease presenilin, mutations in which are associated with one form of familial AD. Depending on the location of processing, Aβ can be liberated either inside or outside the cell. Although the role of the extracellular insoluble plaques has been most intensively investigated, there are indications that soluble cytoplasmic Aβ (particularly Aβ 42) may interact directly with mitochondria, perhaps being imported via the TOM and TIM complexes. Although we do not expect that all the following targets will prove to be relevant to the human disease, Aβ in vitro has been shown to impact on mitochondrial function by inhibiting enzymes of the tricarboxylic acid (TCA) cycle, complex IV, the outer membrane fission protein Fis1 (enhancing mitochondrial fission), cyclophilin D (facilitating the permeability transition), and ABAD (amyloid-binding alcohol dehydrogenase). Increased mitochondrial ROS has also been proposed. Total and mitochondria-associated Aβ 40 and Aβ 42 levels increase with age and are further enhanced in transgenic mice expressing the APP Swedish mutation (K595N/M596L).As with other neurodegenerative disorders, a major challenge is to create an animal model that reproduces the pathology and development of the disease, ideally by targeting the critical upstream initiating sites.
Current models have been developed by reproducing mutations responsible for rare inherited forms of the human disease. Although detailed description of these constructs is beyond the scope of this book, mutations in amyloid precursor (APP), presenilin and tau genes have been explored separately and in combination.One way to disentangle cause and effect is to study the temporal relationships between changes in mitochondrial function, intraneuronal and extracellular accumulation of β-amyloid, neurofibrillary tangles, cell death and cognitive changes. Proteomic studies based on the level of expression of mitochondrial proteins are complicated because although a decrease may indicate a restricted bioenergetic capacity, an increased expression can be interpreted in a similar manner as a compensatory ‘hormetic’ response to a bioenergetic defect, as occurs in MERFF ( Section 12.2.1). Also, values related to mitochondrial protein will obscure changes in total mitochondrial content.Triple transgenic mice (3xTg-AD) incorporating a knockin mutated presenilin 1 gene (M146V) and transgene constructs for the human APP Swedish mutation and human tau (P301L) have become popular models, showing progressive cognitive and pathological changes broadly consistent with the human disease.
Although many other mouse models exist, we focus on these to review some of the bioenergetic approaches that are being taken; however, it must be appreciated that the chances of a human patient presenting with all three mutations is infinitesimal.It is important to establish the sequence of events during the development of pathology in this and other mouse models. Proteomic analysis is ambiguous; at 6 months, blue native gels reveal increased expression of ATP synthase subunits and decreased complex I and IV subunits, while analysis of denatured proteins shows a general increase in a range of mitochondrial proteins. Mitochondrial ‘dysfunction’ and oxidative stress are apparent by 3 months, after which intraneuronal β-amyloid and memory deficits (at 4 months), extracellular β-amyloid plaques and synaptic dysfunction (at 6 months) and finally neurofibrillary tangles (at 12 months) appear sequentially. However, a limitation of many studies is the way in which ‘dysfunction’ is defined and quantified; thus, in one study, dysfunction was defined as a statistically significant decrease in pyruvate dehydrogenase E1α subunits normalised to β-actin and increased oxidative stress by lipid peroxide content of isolated mitochondria. Cultured embryonic hippocampal neurons also displayed decreased spare respiratory capacity. However, this and related studies do not prove that the observed changes in mitochondrial function are causative of the pathology.Mitochondria isolated from specific brain regions have a highly heterogenous origin—from different types of neurons, from glia, and from cell bodies, dendrites, or axons. As a result, interpretation is difficult, while real changes in specific locations can be swamped by the background.
Synaptosomes ( Section 9.6), while still retaining transmitter heterogeneity, can be obtained from animals of any age and allow presynaptic function to be assessed. However, there is no consensus regarding the existence of a significant bioenergetic dysfunction in synaptosomes prepared from AD-model transgenic mice. Although a slight decline in respiratory control ratio was detected in mitochondria further isolated from cortical synaptosomes of ‘Tg mAPP’ mice overexpressing a mutant form of human APP ( Du et al., 2010), in a separate study ( Choi et al., 2012) no difference was detected in the bioenergetic parameters of three other AD-model transgenics after exhaustive control for synaptosomal purity. Amyloid precursor protein (APP) is a type I transmembrane protein expressed in many cell types, including neurons. APP is a 695 amino acid protein with a large ectodomain and relatively short intracellular region. APP has been shown to form homodimers ( Khalifa et al., 2010).
In APP, dimerization is known to be induced by the N-terminal region of APP, referred to as the E1 region ( Fig. 10), which contains a growth factor-like domain and a copper-binding domain (CuBD) ( Soba et al., 2005). A loop formed by disulfide bridges is required for the stabilization of the homodimeric state. Further, juxtamembrane (JM) and transmembrane (TM) regions also participate in homodimerization. APP is processed into smaller fragments, and there are two known catabolic pathways, namely, nonamyloidogenic and amyloidogenic pathways ( Khalifa et al., 2010). APP processing seems to be a critical event in the onset and progression of Alzheimer's disease (AD) ( De Strooper, Vassar, & Golde, 2010) and hence homodimerization of APP and the details of domains and amino acid residues involved in particular domains are studied in detail.
In AD, the main component of plaques is the amyloid beta (Aβ) peptides with 40–42 amino acids ( Masters et al., 1985). These peptides are released from a precursor protein APP by sequential cleavage by beta-site APP-cleaving enzyme 1 (BACE1) and by the γ-secretase complex. Cleavage of APP that consists of 695 amino acids by BACE1 releases the large ectodomain of APP and membrane-anchored C-terminal APP fragment (CTF) of 99 amino acids.
The 99 amino acid polypeptide will undergo further cleavage by γ-secretase resulting in Aβ peptides of various lengths. APP intracellular domain (ICD) is released into the cytosol ( Eggert, Midthune, Cottrell, & Koo, 2009; Jung et al., 2014; Vassar et al., 1999).
It was proposed that dimerization of TM domain and amino acids in the TM domain is important in this cleavage process. APP contains three glycine-xxx-glycine (GxxxG) motifs at the extracellular JM/TM boundary. It is reported that the GxxxG motifs in the APP TM domain participate in dimerization and this domain is located in the region where cleavage occurs.
Structural studies on the APP JM/TM region in isolation showed that the GxxxG motifs mediate TM helix homodimerization of the protein in the lipid bilayer ( Sato et al., 2009; Fig. Mutational studies by the introduction of a cysteine residue at the junction of the JM/TM region were shown to form stable dimers linked by disulfide bridges. The stabilization of dimerization leads to increased Aβ production ( Scheuermann et al., 2001). Aβ is produced as a stable dimer, indicating that the amyloidogenic secretases (β and γ) are able to process APP under its dimeric form. Thus, dimerization seems to help Aβ production. The motifs involved in dimerization of C-terminal APP fragments (CTFs) are also responsible for the packing of Aβ peptides into protofibrillar structures ( Sato et al., 2006).
The glycines present in GxxxG motifs are important in the PPI of TM helices as well as in the formation of the cross β-sheet structures found in the Aβ fibrils. The GxFxGxF framework seems to be the hot spot for designing drug-like molecules for AD. Peptides can be designed to disrupt sheet-to-sheet packing and inhibit the formation of mature toxic Aβ fibrils.
Antibodies mapping to an epitope in this Aβ region are also able to significantly reduce the accumulation of intracellular Aβ, which is known to be highly neurotoxic ( Tampellini et al., 2007). Thus, the dimerization process, the GxxxG motifs, the details of structure in the dimerization region, and the cleavage of this region by secretase are important in designing drugs for AD.
Richter et al. (2010) have studied the molecular mechanism of γ-secretase modulators such as sulindac sulfide and indomethacin and, using molecular docking studies, have suggested that these compounds bind at the smooth surface provided by glycines arranged in GxxxG motifs ( Richter et al., 2010). Schematic representation of different domains of APP that form homodimers. Arrows indicate the proposed dimerization regions. CAPP, central APP domain; CuBD, copper-binding region; GFLD, growth factor-like domain; ICD, intracellular domain; JM, juxtamembrane region; KPI, Kunitz protease inhibitor domain; TM, transmembrane region.
Schematic diagram is drawn based on Khalifa, N. B., Van Hees, J., Tasiaux, B., Huysseune, S., Smith, S. O., Constantinescu, S. What is the role of amyloid precursor protein dimerization? Cell Adhesion & Migration, 4(2), 268–272; Eggert, S., Midthune, B., Cottrell, B., & Koo, E. Induced dimerization of the amyloid precursor protein leads to decreased amyloid-beta protein production.
The Journal of Biological Chemistry, 284(42), 2. (2007) have shown that γ-secretase processivity is reduced when CTFβ forms dimers, because of interactions of TM domain GxxxG motifs. This leads to the formation of fragments of Aβ isoforms which are larger in size compared to 40 amino acid Aβ. There are reports indicating that APP CTFβ dimers are not γ-secretase substrates. (2014) studied the importance of residues at the interface of APP ectodomain and TMD by mutating the lysine residues at the interface of the APP ectodomain and transmembrane domain (TMD) and evaluated the Aβ production.
Based on their studies, they concluded that the monomeric form of the mutant increased long Aβ production without altering the initial ɛ-cleavage utilization, whereas dimeric forms of APP are not efficient γ-secretase substrates and primary sequence determinants within APP substrates alter γ-secretase processivity. Thus, there is controversy regarding the dimerization of APP and its link to cleavage of APP by γ-secretase. The design of inhibitors of APP has to be carefully considered when targeting a particular region of APP that helps for homodimerization. Amyloid precursor protein (APP), an evolutionary conserved type 1 transmembrane protein, is unequivocally linked to AD pathogenesis as the unique source of neurotoxic forms of Aβ ( Chen, 2015; Rajendran and Annaert, 2012). During early development, APP is highly enriched at the growth cones of developing neurites ( Ramaker et al., 2016; Sabo et al., 2003). In more mature neurons, APP localizes to focal adhesion sites and within pre- and postsynaptic structures of the central and peripheral nervous tissue, suggesting a functional role in neuritic growth and synaptic plasticity ( Ashley et al., 2005; Yamazaki et al., 1997).
APP is synthesized in the ER and transported to the Golgi apparatus where it is packaged into vesicles for delivery to the cell surface for further processing by α-, β-, and γ-secretases following the non-amyloidogenic (constitutive) or amyloidogenic pathway ( Fig. 3) ( O’Brien and Wong, 2011; Ramaker et al., 2016). The non-amyloidogenic pathway leads to the production of non-pathogenic fragments, while the amyloidogenic pathway promotes the generation of Aβ peptides.
Briefly, following the former pathway, APP is first cleaved by α-secretase within the Aβ sequence, thereby blocking Aβ production, to generate two proteolytic fragments: soluble APPα, and the corresponding C-terminal fragments, α-CTF/C83 (a protein stub that remains secured to the plasma membrane for further proteolytic processing) ( Gandy et al., 1994; Roychaudhuri et al., 2009). Soluble APPα is recycled back to the cell surface by the recycling compartments or delivered to the lysosome for degradation through the endosomal–lysosomal system ( Caster and Kahn, 2013; Golde et al., 1992). In the amyloidogenic pathway, APP is cleaved by β-secretase, the major secretase in the brain, at the N-terminus of the Aβ sequence, thus generating soluble APPβ, and the corresponding C-terminal fragment, β-CTF/C99 (a membrane-associated fragment comprising the entire Aβ sequence). Both C99 and C83 are subsequently cleaved by ץ-secretase within the transmembrane domain, resulting in the release of a nontoxic p3 fragment, APP intracellular domain, and Aβ peptide species of slightly different lengths ( Fig. 3) ( Cole and Vassar, 2007; Jarrett et al., 1993). With β- amyloid precursor protein, axonal spheroids are detected within the necrotic lesions of PVL, whether focal or large ( Fig.
30,31 This finding is not unexpected in view of the injury to all cellular elements in the focal areas of necrosis. However, surprisingly perhaps, in the more diffuse nonnecrotic component of PVL, evidence for axonal injury has recently been gathered.
With the apoptotic marker fractin, diffuse axonal injury is detected in the white matter distant from acute or organizing necrotic foci, suggesting a widespread axonopathy in PVL ( Fig. 30,31 This diffuse axonal damage could reflect secondary degeneration of thalamocortical afferents complicating primary thalamic neuronal loss. Alternatively, hypoxic-ischemic or inflammatory injury directly to the axon, with secondary impairments in axonal-OL interactions in the initiation and maintenance of myelination, seems possible (see later). Irrespective of its pathogenesis, widespread axonal damage likely contributes to the reduced white matter volume and callosal thinning in end-stage PVL.
Axonal injury throughout the diffuse and focal components of PVL may also lead to architectonic changes in the overlying cerebral cortex. The amyloid precursor protein (APP) is pivotal in the pathophysiology of Alzheimer’s disease since its abnormal cleavage by β-secretase and γ-secretase generates β-amyloid peptide, which aggregates into neurotoxic amyloid plaques in the brain tissues. Therefore, agents capable of mitigating APP have the potential to withhold the progression of AD, and such agents may come from medicinal plants. In fact, such agents have been identified by Xia et al. 31 as the amide alkaloids piperlonguminine and dihydropiperlonguminine ( CS 1.10) from Piper kadsura (Choisy) Ohwi, which inhibited the level of APP in human SK-N-SH neuroblastoma cells at a dose of 13.1 μg/mL 31 and raised the exiting possibility of isolating amide alkaloids from members of the vast genus Piper L. For the stabilization of AD.
The neuroprotective potential of amide alkaloids from the genus Piper L. Is further demonstrated with piperine ( CS 1.11) from Piper nigrum L. (family Piperaceae Giseke), which protected rodents against ethylcholine aziridinium (AF64A) ion-induced dementia and neuronal loss. 32 The biochemical mechanism underlying the neuroprotective effects of piperine is still elusive, but one could reasonably speculate that the inhibition of monoamine oxidase (MAO) is involved.
33 Indeed, piperine inhibited the enzymatic activity of monoamine oxidases A (MAO-A) and B (MAO-B) with an IC 50 value equal to 0.4 μM and 0.2 μM, respectively, 34 and the structure activity relationship demonstrates that the ketone moiety, the two double bonds, and the piperine heterocycle are necessary for activity against MAO-A. 34 MAO-A is a critical enzyme in the pathophysiology of Parkinson’s disease because it interacts with the endogenous dopamine-derived neurotoxin N-methyl-(R)-salsolinol, which causes cell death in dopaminergic neurons. 35 Indeed, the binding of N-methyl-(R)-salsolinol to MAO-A favors the opening of mitochondrial permeability transition pore (MPT), hence mitochondrial insult, release of cytochrome c, activation of caspase 3, and apoptosis. 36 Furthermore, the piperine derivative (E,E)-1-5-(3,4-dihydroxyphenyl)-1-oxo-2,4-pentadienylpiperidine (HU0622, CS 1.12) at a dose of 7 μM activated ERK1/2 in rat pheochromocytoma (PC12) cells and induced neurite outgrowth 37 via probable activation of cAMP response element binding protein (CREB). 38 Note that the amide alkaloid bastadin 9 ( CS 1.13), isolated from the sponge Ianthella basta Pallas (family Lanthellidae), inhibited the enzymatic activity of β-secretase against APP with an IC 50 value equal to 0.3 μM.
39 Such compounds also have the captivating potential to block the neurotoxic accumulation of Ca 2+, for example NP04634 ( CS 1.14), the derivative of 11,19-dideoxyfistularin from the sponge Aplysina cavernicola Vacelet (family Aplysinidae), which, at a concentration 10 μM, protected bovine chromaffin cells exposed to 0.3 μM of L-type Ca 2+ channel activator. In the past few decades, observations were made that a series of 1-benzyl- 4-ethylpiperidine derivatives elicited potent anti-AChE activities, such as 1-benzyl-4-2-( N-benzoylamino)ethylpiperidine, and 3g, 3h, and 3p ( CS 1.15–1.18).
41 These exciting activities heralded a rapid increase in structure activity relationship and synthesis of analogs and resulted in the discovery of donepezil ( CS 1.19), which inhibited AChE with an IC 50 value equal to 5.7 nM and was developed as a drug for the treatment of AD. Bakhoum, George R. Jackson, in, 2011 B Aβ AmyloidMutations in the amyloid precursor protein (APP) cause familial AD.
26 Amyloid plaques are mainly composed of Aβ40 or Aβ42 amino acid peptides derived from APP cleavage.Amyloidogenic Aβ peptides arise from APP cleavage through β- and γ-secretase. 27 Presenilins, which have a single fly homolog (Psn), are a component of the γ-secretase complex. Mutations in PS1 and PS2 cause early onset familial AD. 26 Drosophila homologs of other components of the γ-secretase, including nicastrin, Pen-2, and Aph-1, have been identified. 28 The fly homolog of β-secretase, dBACE, has been identified recently 29; this enzyme cleaves human APP at a different site than that at which human β-secretase acts. However, dBACE overexpression cleaves dAPPl, the APP fly homolog, and produces an amyloidogenic form that aggregates.
It is noteworthy that dAppl does not contain the Aβ domain found in human APP. This suggests that although the sequence is not conserved between humans and Drosophila, amyloidogenic processing may still be conserved. 29 dAPPl may function similar to APP, since large deletions of dAppl result in reduced locomotion and phototaxis deficiency that are rescued by human APP.
30Aβ toxicity in flies also has been modeled by directed overexpression of Aβ fragments. Aβ 1–42 (but not Aβ 1–40) overexpression reduces lifespan in the fly.
However, both Aβ fragments cause progressive loss of associative learning. Aβ overexpression in the eye causes retinal phenotypes. 31 Moreover, Aβ overexpression causes long-term depression.
Chiang et al. Showed through immunostaining of PI3K that Aβ induces PI3K hyperactivity.
Knockdown or pharmacologic inhibition of PI3K function leads to rescue of the long-term depression phenotype. 32 Crowther et al. Reported that Aβ forms nonamyloidogenic aggregates that resemble diffuse plaques. Immunohistochemistry using a conformation-dependent antibody indicates that oligomers may actually be the entities mediating neurotoxic effects.
33 The downstream effects of Aβ have not been identified with certainty, although recent findings suggest tau phosphorylation to be an important downstream effect of Aβ-induced neurotoxicity. A recent paper by Iijima et al. Showed that coexpression of Aβ42 with tau increased tau phosphorylation at Ser262, an AD-related phosphoepitope. 34 Ser262 phosphorylation enhanced tau-induced neurotoxicity, whereas coexpression of Aβ42 and a nonphosphorylatable form of tau, Ser262Ala, did not cause any neurodegenerative phenotypes. Grace Zhai, in, 2015 54.5.4 Interactions of Tau and Other Toxic Molecules in DrosophilaIn AD, the amyloid precursor protein (APP) and Tau, two seemingly unrelated proteins, are respectively the key components of two important pathological hallmarks, amyloid plaques and NFTs.
Research related to AD has shown that Aβ (or Abeta), the predominant component of amyloid plaques, induces Tau phosphorylation in mammals ( Busciglio et al., 1995). Further studies have also indicated that another component of amyloid plaques, apolipoprotein E4, increases Tau phosphorylation and induces the formation of intracellular NFTs ( Huang et al., 2001). In Drosophila, it has been shown that overexpression of Appl, the Drosophila homologue of APP, along with bovine Tau (bTau) by pan-neural driver ApplG1a-GAL4 and Elav C155 -GAL4 results in the defects of axonal transport in larval motor neurons and neuroendocrine dysfunction, including lethality at the pharate adult stage and “juvenile” loss of wing phenotype at the adult stage ( Torroja et al., 1999). Groups of studies have been reported that Aβ42, the longer cleavage of the APP processed by γ-secretase, increases Tau toxicity in Drosophila ( Folwell et al., 2010; Fulga et al., 2007).
Have shown that coexpression of Aβ42 and hTau in transgenic flies exacerbates the hTau-induced rough eye phenotype and vacuolization in the brain. They also suggested that this synergistic interaction between Aβ42 and Tau requires the intact SP/TP sites of Tau because the alteration of hTau, either the phosphodeficient (hTau AP) or phosphomimetic (hTau E14), does not have a dramatic toxic effect on the Drosophila vision system ( Fulga et al., 2007). Another study by Folwell et al. Has shown that Aβ42 strongly increases Tau-induced neuronal toxicity by disrupting axonal transport and synaptic structure, leading to behavior impairments and reduced lifespan ( Folwell et al., 2010). Interestingly, it was shown that treating the transgenic flies coexpressing A β 42 and hTau with lithium chloride diminishes the aggravated effect of Aβ42 on hTau phosphorylation, which indicates that the GSK-3βsignal pathway may be involved in the interaction between Aβ42 and hTau to cause Tau-mediated neuronal toxicity ( Folwell et al., 2010). Chk2 from the DNA repair pathway is another possible mechanism involved in Aβ42-mediated hTau phosphorylation ( Iijima-Ando et al., 2010; Iijima et al., 2010).
Precursor Activation Example For Kids
It has been shown that Tau Ser262, one of the important phosphorylation SP/TP sites and the target site of the DNA damage-activated kinase (Chk2) ( Iijima-Ando et al., 2010), is phosphorylated in the Drosophila model of AD, and the phosphodeficient mutation of Ser262 has been shown to alleviate Aβ42-induced Tau toxicity ( Iijima et al., 2010). However, in Aβ42 transgenic fly brains, many genes involved in the DNA repair pathways including Chk2 are upregulated, and the induction of a DNA repair response protects against Aβ42 toxicity, which indicates that activation of DNA repair pathways is protective against Aβ42 toxicity but may trigger hTau phosphorylation and toxicity in AD pathology ( Iijima et al., 2010).
Chemisorption is a kind of which involves a chemical reaction between the surface and the adsorbate. New chemical bonds are generated at the adsorbant surface. Examples include macroscopic phenomena that can be very obvious, like, and subtler effects associated with, where the catalyst and reactants are in different phases. The strong interaction between the and the creates new types of electronic.In contrast with chemisorption is, which leaves the chemical species of the and surface intact. It is conventionally accepted that the energetic threshold separating the of 'physisorption' from that of 'chemisorption' is about 0.5 eV per adsorbed.Due to specificity, the nature of chemisorption can greatly differ, depending on the chemical identity and the surface structural properties.