Review Arginine metabolising enzymes as targets against Alzheimers’ disease Chris G. Whiteley ⇑ Graduate Institute of Applied Science & Technology, National Taiwan University of Science and Technology, Taipei, Taiwan article info Article history: Received 30 December 2013 Received in revised form 26 January 2014 Accepted 28 January 2014 Available online 4 February 2014 Keywords: Alzheimers disease Arginine metabolizing enzymes Neuronal nitric oxide synthase Peptidyl arginine deiminase Inhibition Fibrillogenesis Mechanisms abstract Even though the accumulation of arginine and the deposit of aggregated Ab-peptides (senile plaques) in the brain of an Alzheimer patient are classic points of evidence in the neuropathology of the disease con- siderable dispute remains on their method of formation. One acceptable mechanism to initiate events is a ‘seed’ aggregation of free monomeric peptides into toxic soluble amyloid oligomers and subsequently into deposits of insoluble fibrils. Since all of these events take place in the brain astrocytes it suggests an interference between arginine-metabolising enzymes and the Ab-peptides. Through kinetic, fluorimet- ric and thermodynamic analyses two such enzymes – neuronal nitric oxide synthase and peptidyl argi- nine deiminase – are, not only inhibited by structural fragments of Ab 1–42 but are catalytic towards fibrillogenesis. The interaction of the peptide fragments with each enzyme is endothermic, non-sponta- neous and involves hydrophobic–hydrophobic associations with a single binding site. The trigger for this series of events focusses in particularly on Ab 17–21 with two phenylalanines [Phe 19 ; Phe 20 ], the three gly- cine zipper motifs [Ab 25–29 ;Ab 29–33 ;Ab 33–37 ] and the triple sequence [Ab 25–37 ] that includes two isoleu- cine residues [Ile 31 ; Ile 32 ]. FRET studies show the Ab-peptide fragments bind to the enzymes <3.0 nm from a single surface tryptophan. Free Ab monomers bind to an enzyme, formulate a nucleus, initiate their aggregation and subsequently become entrapped and couple to the existing aggregated monomers, leading to an elongated fibril. Silver and gold nanoparticles reverse fibrillogenesis! They are surrounded by the amyloid peptide molecules in vivo to effectively deplete their concentration. This does not allow any ‘lag’ time, nor prevent the formation of critical nuclei for the initial association phase and, inevitably, prevent fibril initiation and elongation. This review focusses on the function and action of arginine met- abolising enzymes with respect to the formation of senile plaques and amyloid peptide aggregation to facilitate more of an understanding of neurodegeneration in Alzheimer disease. Ó 2014 Elsevier Ltd. All rights reserved. Contents 1. Introduction .......................................................................................................... 24 2. Arginine metabolising enzymes (AME) ..................................................................................... 24 2.1. Neuronal nitric oxide synthase (nNOS) ............................................................................... 24 2.2. Peptidyl arginine deiminase (PAD) ................................................................................... 24 3. Enzyme Ab-peptide fragment interactions .................................................................................. 24 3.1. Kinetic analysis: inhibitions ........................................................................................ 24 3.2. Fluorimetric analysis: fibrillogenesis ................................................................................. 26 3.3. Fluorescence resonance energy transfer (FRET)......................................................................... 27 3.4. Thermodynamic analysis .......................................................................................... 28 4. Inhibiting/reversing fibrillogenesis ........................................................................................ 28 4.1. Ag/Au nanoparticles .............................................................................................. 28 5. Mechanistic aspects .................................................................................................... 28 6. Concluding comments .................................................................................................. 29 References ........................................................................................................... 29 http://dx.doi.org/10.1016/j.neuint.2014.01.013 0197-0186/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Tel.: +886 2 2737 6939; fax: +886 2 2730 3733. E-mail address: [email protected]Neurochemistry International 67 (2014) 23–31 Contents lists available at ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci
Transcript
Neurochemistry International 67 (2014) 23–31
Contents lists available at ScienceDirect
Neurochemistry International
journal homepage: www.elsevier .com/locate /nci
Review
Arginine metabolising enzymes as targets against Alzheimers’ disease
http://dx.doi.org/10.1016/j.neuint.2014.01.0130197-0186/� 2014 Elsevier Ltd. All rights reserved.
Even though the accumulation of arginine and the deposit of aggregated Ab-peptides (senile plaques) inthe brain of an Alzheimer patient are classic points of evidence in the neuropathology of the disease con-siderable dispute remains on their method of formation. One acceptable mechanism to initiate events is a‘seed’ aggregation of free monomeric peptides into toxic soluble amyloid oligomers and subsequentlyinto deposits of insoluble fibrils. Since all of these events take place in the brain astrocytes it suggestsan interference between arginine-metabolising enzymes and the Ab-peptides. Through kinetic, fluorimet-ric and thermodynamic analyses two such enzymes – neuronal nitric oxide synthase and peptidyl argi-nine deiminase – are, not only inhibited by structural fragments of Ab1–42 but are catalytic towardsfibrillogenesis. The interaction of the peptide fragments with each enzyme is endothermic, non-sponta-neous and involves hydrophobic–hydrophobic associations with a single binding site. The trigger for thisseries of events focusses in particularly on Ab17–21 with two phenylalanines [Phe19; Phe20], the three gly-cine zipper motifs [Ab25–29; Ab29–33; Ab33–37] and the triple sequence [Ab25–37] that includes two isoleu-cine residues [Ile31; Ile32]. FRET studies show the Ab-peptide fragments bind to the enzymes <3.0 nmfrom a single surface tryptophan. Free Ab monomers bind to an enzyme, formulate a nucleus, initiatetheir aggregation and subsequently become entrapped and couple to the existing aggregated monomers,leading to an elongated fibril. Silver and gold nanoparticles reverse fibrillogenesis! They are surroundedby the amyloid peptide molecules in vivo to effectively deplete their concentration. This does not allowany ‘lag’ time, nor prevent the formation of critical nuclei for the initial association phase and, inevitably,prevent fibril initiation and elongation. This review focusses on the function and action of arginine met-abolising enzymes with respect to the formation of senile plaques and amyloid peptide aggregation tofacilitate more of an understanding of neurodegeneration in Alzheimer disease.
24 C.G. Whiteley / Neurochemistry International 67 (2014) 23–31
1. Introduction
Deposits of insoluble b-amyloid (Ab) aggregates [senile plaques]in the astrocyte (neuroglial) cells in the human brain is a classicobservation of the neuropathology of Alzheimer’s disease (AD)(Soto et al., 1994, 1995; Findeis, 2007; Yi et al., 2009) a fatal neu-rodegenerative disorder associated by an impairment of dailyactivities, behaviour disturbances and a variety of neuropsychiatricsymptoms (de Meyer et al., 2006). In order to understand the dis-ease, both medically and scientifically, it is paramount to under-stand the mechanism of the formation of these senile plaques,which, to date, remains elusive. The higher the concentration ofAb in vivo the greater the probability they would aggregate intoinsoluble senile plaques and/or fibrils. Consequently any accumu-lation of these peptides in the astrocytes of the brain must actuallyimply a decrease in Ab catabolism. Furthermore amyloid fibrils canbe assembled through either self-induction or by a proteolyticmechanism, manifested by p–p and hydrophobic–hydrophobicinteractions of relevant amino acid side chains (Soto, 2001; Sotoet al., 2007; Ferreira and de Felice, 2001). It is well known thatAb1–40/42 and the neurotoxic Ab25–35 fragment are capable of gener-ating such fibrils (Iwata et al., 2000a; Gorevic et al., 1987; Pikeet al., 1995) and neurotoxic oligomers (Gruden et al., 2007).
The astrocytes in the diseased brain have another function – tostore the amino acid arginine – but whether this function is as a re-sult, or a cause, of AD remains unclear (Poulos et al., 2002). The factthat there is a low level of citrulline and a high level of arginine inthe cerebrospinal fluid of AD patients (Yi et al., 2009) could meanthat there is a decrease in the levels of enzymes that metabolizesthis amino acid. In the etiology and pathogenesis of AD it is logical,therefore, to investigate arginine-metabolising enzymes (AME) andtheir intimate association with deposits of the amyloid peptides.
2. Arginine metabolising enzymes (AME)
2.1. Neuronal nitric oxide synthase (nNOS)
One such enzyme is neuronal nitric oxide synthase (nNOS) [EC.1.14.13.39] an enzyme that oxidises L-arginine to L-citrulline andnitric oxide (NO) an important signaling molecule in the brain(Fig. 1A) (Poulos et al., 2002). The enzyme consists of an N-terminaloxygenase domain that contains binding sites for L-arginine, hemeand tetrahydro-L-biopterin (H4B) and a C-terminal reductase do-main that binds FAD, FMN and NADPH aligned head to head(Fig. 1B–E) with a short calmodulin (CaM) linker. The nNOS-cata-lyzed conversion of L-arginine to L-citrulline and nitric oxide isthe sum of two oxidation reactions – arginine to N-hydroxyargi-nine then into citrulline and nitric oxide (Campos et al., 1995) –and requires a sequential transfer of three electrons between thereductase and oxygenase domains. The nitrogen of NO is derivedfrom the guanidino nitrogen atoms of L-arginine while the oxygenis derived from molecular oxygen (Bruckdorfer, 2005). The reduc-tase domain converts NADPH into NADP+ and feeds electrons viaFAD or FMN (either one of the flavin cofactors are necessary forcatalysis) to an iron site in the oxygenase domain. The heme (Fe)center and H4B in the oxygenase domain converts arginine andoxygen into citrulline and NO. It must be noted that electron flowthrough the reductase domain requires the presence of bound cal-cium ion or calmodulin (Ca2+/CaM) (Knowles et al., 2001).
2.2. Peptidyl arginine deiminase (PAD)
A second enzyme is peptidylarginine deiminase (PAD II)[EC.3.5.3.15], a post-translationally modified enzyme that convertsprotein–arginine into protein–citrulline and ammonia (Fig. 2). Of
the five different isozymes for this enzyme PADII is expressed inthe brain where a major substrate target is myelin basic protein(MBP), a constituent of the myelin sheath (Pritzker et al., 2000a,2000b) and astrocytes (Bologa et al., 1985). Citrullination of MBPby PADII is, therefore, likely to play a key role in the pathogenesisof neurodegenerative disease (Musse et al., 2008).
3. Enzyme Ab-peptide fragment interactions
A thorough investigation on the interaction of several Ab-pep-tide fragments [Ab1–40, Ab22–35, Ab17–28, Ab32–35, Ab25–35, Ab1–42,Ab25–29, Ab17–21, Ab29–33, Ab33–37, Ab25–37] and pseudo Ab-peptidesAb17–21r, Ab17–21p, Ab29–33r, Ab29–33p (Fig. 3) with nNOS Padayacheeet al., 2012, 2013; Padayachee and Whiteley, 2011, 2013a,b) andPAD (Louw et al., 2007; Mohlake and Whiteley, 2010) has beenundertaken. Kinetic analysis establish parameters (Vmax, Km, Ki)while the binding constants for the formation of soluble aggregatesand insoluble fibrils are estimated by the Congo Red assay (Klunket al., 1989), fluorescence quenching and Thioflavin-T stainingfluorescence (Evans et al., 1995; Naiki et al., 1991; le Vine, 1993,1999). A thermodynamic analysis at different temperatures assessenthalpies (DH), entropies (DS) and Gibbs free energy (DG) profilesto indicate the spontaneity of reactions and mechanism ofaggregation.
3.1. Kinetic analysis: inhibitions
Incubation of nNOS with each Ab-peptide decrease its activitywithin the first minute followed by a gradual restoration of activityto 100% after 5–10 min (Padayachee and Whiteley, 2011, 2013a).With PAD these time scales were distinctly slower (Louw et al.,2007). This time-dependence suggests an association – dissocia-tion between nNOS and/or PAD and the amyloid peptide fragmentof which the strength and time of effect is dependent not only onthe type of the fragment but on the actual enzyme as well. Further-more it points to the fact that the ‘AME’ act as catalysts and convertthe amyloid peptide into a form that is no longer capable of bind-ing. It is well documented that Ab peptides interact in hydrophobicenvironments (Kanski et al., 2002; Soreghan et al., 1994) lendingsupport for hydrophobic–hydrophobic associations between theamyloid peptides and nNOS and/or PAD. Examining the amino acidsequence of the Ab-peptides with favourable inhibitor constants(Ki) points towards the hydrophobic pentapeptide patch Ab17–21
and the glycine zipper motifs A25–29, Ab29–33 and Ab33–37. TheAb17–28 fragment contains two phenylalanines [Phe19, Phe20] andtwo polar residues [Glu22 and Asp23] (Fig. 3) and since the inhibitorconstant (Ki) of this fragment is greater than that of the Ab17–21
fragment it suggests, with respect to a structure-binding-inhibi-tory protocol, that polar residues are not important while aromaticamino acids and their associated p–p interactions are fundamen-tally strategic (Jones and Mezzenga, 2012). The Ab29–33 fragmentwith its pair of isoleucines [Ile31 and Ile32] also shows a greaterKi value Ab32–35 [single isoleucine] or Ab33–37 [zero isoleucine]and suggests that the hydrophobic character of the pair of isoleu-cines is also strategically important as far as initial interaction isconcerned.
To add further fuel to this strategic thinking four pseudoAb-peptides fragments, with altered amino acid sequences,(Fig. 3) – the reverse-sequenced peptides [Ab17–21r:AFFVL; Ab29–33r:GIIAG] and peptides with, respectively, both phenylalanines andboth isoleucines substituted with polar glutamic acid residues[Ab17–21p:LVEEA; Ab29–33p:GAEEG] when interacted with nNOS(Padayachee and Whiteley, 2013a) support this claim. Notwith-standing that even with the reverse sequenced peptides one ofthe phenylalanines and/or isoleucines remain in the same position
NH2 COOHARG HEME BH4 FMN FAD NADPH
CaM
OXYGENASE DOMAIN REDUCTASE DOMAIN
L-Arginine N-Hydroxy-L-Arginine L-Citrulline
A
B
Arginine Substrate
Tetrahydro-L-Biopterin
Heme
C
N-Hydroxy Arginine Heme
NO
Tetrahydro-L-Biopterin
FMNFAD
NADP
NO
D
E
Fig. 1. (A) Enzymatic reaction for neuronal nitric oxide synthase (nNOS). (B) Scheme describing the individual components for the oxygenase and reductase domains showingthe calmodulin (CaM) linker. (C) Structure of the oxygenase domain for nNOS [PDB:1OM4] showing the heme, arginine substrate and tetrahydro-biopterin. (D) Structure ofthe oxygenase domain for nNOS [PDB:1OM4] showing the heme, intermediate N-hydroxy-arginine, nitric oxide (NO) and tetrahydro-biopterin. (E) Structure of the reductasedomain for nNOS showing the FAD, FMN and NADP.
C.G. Whiteley / Neurochemistry International 67 (2014) 23–31 25
Trp190
Trp108
Trp83
Trp27
A
B
Fig. 2. (A) Enzymatic reaction for peptidyl arginine deiminase (PADII). (B) Structureof the PAD showing relevant tryptophan residues.
26 C.G. Whiteley / Neurochemistry International 67 (2014) 23–31
it reinforces that both phenylalanine and both isoleucine residuesin Ab17–21 and Ab29–33 are crucial for initial binding to the enzymesand subsequent inhibition. Other pseudopeptides have also been
Asp1
Gly25
Gly29
Ala21
Gly3
Phe1Phe20
Phe1Val20 Leu21
Glu1Glu20 Ala21
Ala30 Ile31 Ile32
Gly29 Ile30 Ile31 Ala32 Gly33
Gly29 Ala30 Glu31 Glu32 Gly3
Ala2 Glu3 Phe4 Arg5 His6 Asp7
Glu22 Asp23
Val24
Ser26
Asn27
Lys28
Fig. 3. The amino acid sequence of Ab1–42. Residues indicate pseudo-peptides witsubstituted for Phe19 and Phe20 or Ile31 and Ile32.
designed with the aim of disrupting hydrogen bonding thatstabilizes the b-sheet structure. The five residue b-sheet breakerpeptide, (Ac-Leu–Pro–Phe–Phe–Asp–NH2) capped with N- and C-terminal protection, and having a proline and aspartic residuesubstituted for valine and alanine show that the proline residuein this peptide inhibited b-sheet formation (Soto et al., 1998; Soto,1999).
The zipper motifs look especially promising in view of the G-X-X-X-G protein/protein recognition motif that are identified inmany proteins as a transmembrane helix-turn-helix (Kim et al.,2005; Fonte et al., 2011) and consequently may play an importantrole in the etiology and pathophysiology for AD (Berharnu andHansmann, 2012).
3.2. Fluorimetric analysis: fibrillogenesis
The form of the Ab-peptide that is no longer capable of bindingto the enzymes is an aggregated fibril, first soluble, identified byCongo Red assay (Klunk et al., 1989) then insoluble, identified bythioflavin-T fluorescence (Evans et al., 1995; Naiki et al., 1991; leVine, 1993, 1999). The rate of formation of soluble fibrils and theirconversion into an insoluble form are dependent on the enzymeand structure of amyloid peptide (Padayachee et al., 2012; Moh-lake and Whiteley, 2010; Padayachee and Whiteley, 2011, 2013a,2013b) Ab32–35 has a limited effect with this fibril interconversionleaving over 50% soluble fibrils after 96 h. When no enzyme is pres-ent there is no formation of fibrils either soluble or insoluble. Thisnot only offers supporting evidence that the enzymes are indeedcatalytic towards fibril formation, but indicate a direct estimationof both the concentration and rate of formation of fibrils. In generalterms PAD is considerably slower than nNOS in initiating the tran-sition between soluble and insoluble fibrils. The latter enzymeforms insoluble fibrils from all of the amyloid fibrils within30 min from the start of incubation and is usually complete(100%) within 72–96 h. PAD, on the other hand, starts to convertsoluble to insoluble fibrils at about 24 h and is complete only after120 h.
Val12
Leu17
3 Gly37
Ala42
Val18 9
Ala17 Phe18 9
Leu17 Val18 9
3
Ser8 Gly9 Tyr10 Glu11
His13
His14 Lys16
Leu34 Met35 Val36 Gly38
Val39
Val40
Ile41
Gln15
h a reversed sequence; residues indicate pseudo-peptides with glutamic acid
C.G. Whiteley / Neurochemistry International 67 (2014) 23–31 27
The number of binding sites (n) on each enzyme available forthe amyloid peptides is one in all cases. Furthermore a strong asso-ciation exists between the nNOS or PAD and Ab17–21, A25–29, Ab29–33
and Ab33–37 as estimated by the association constants (Ka) (Padaya-chee and Whiteley, 2013a, 2013b; Louw et al., 2007; Mohlake andWhiteley, 2010). Any amyloid peptide with an altered sequence tothat of the standard one (Fig. 3) – especially if polar glutamic acidresidues are substituted – show weaker association constants anddo not interact favorably with the enzyme. This is further evidencefor the importance of residues Phe19, Phe20, Ile31, and Ile32 in theinitiation of fibrillogenesis. Since the binding constants increaseas temperature increases the interaction of the amyloid peptideswith nNOS is endothermic (Padayachee and Whiteley, 2013a,b).
The micro-environment for molecular recognition of Ab-peptideinteraction with biological macromolecules is also investigated bythe quenching of tryptophan fluorescence and involves an investi-gation of hydrogen bonds, van der Waals forces as well as electro-static and hydrophobic interactions. The ease of accessibility of theAb-peptide fragments to the fluor (tryptophan) molecules withinthe enzymes leads to a quenching of the fluorescence monitoredby the Stern–Volmer constants (KSV). These values for nNOS-Ab-peptides indicate that Ab17–21, Ab17–28 and the three glycine zippermotifs [G-X-X-X-G] [Gly25–Gly29]; [Gly29–Gly33]; [Gly33–Gly37]show substantial quenching abilities with comparable easy accessto surface tryptophans compared to the value for Ab32–35. This sup-ports claims that these particular fragments are critical in the ini-tial interaction of the amyloid peptide fragments with the enzyme.Both of the reverse sequenced ‘pseudo’ amyloid peptides frag-ments [Ab17–21r; Ab29–33r] and the more polar substituted ones[Ab17–21p; Ab29–33p] show insubstantial fluorescence quenchingwith a more restricted influence on the surface tryptophan fluors.
Amyloidogenicity is a common property of proteins and pep-tides (Dobson, 2004; Fandrich et al., 2003; Kallberg et al., 2001;Woo et al., 2011; Carlo, 2010) and the Ab-peptides themselvespossess several criteria to initiate fibrillogenesis (Serpell, 2000).The N-terminus (Fig. 3) is important for initiating a–b conforma-tional switching; the hydrophobic residues 17–21 and 29–37 arethe major b-sheet regions and function as key determinants in
Arginine Substrate
Heme
Tetrahydro-L-Biopterin
Trp716
ërí = 2.35 nm
Quencpeptid
Fluor
Arginine Substrate
Heme
Tetrahydro-L-Biopterin
Trp716
ërí = 2.35 nm
Quencpeptid
FluorA
Fig. 4. Illustrative diagram for neuronal nitric oxide synthase (nNOS) with heme and tetsingle surface Trp716 donor fluorophore. (B) FRET analysis with suggested position of flu
aggregation (Kammerer et al., 2004; Akkermans et al., 2006; DaS-ilva et al., 2010); the aromatic residues [Phe19, Phe20] contributein p–p stacking interactions in the b-sheet enhancing the forma-tion of fibrils (Jones and Mezzenga, 2012).
3.3. Fluorescence resonance energy transfer (FRET)
Fluorescence energy transfer [FRET] (Clegg, 1995, 1996) is acommon technique not only for measuring the exact position ofthe amyloid peptide within the active site of nNOS and/or PADbut also for examination of enzyme structure and conformationalchanges induced on binding. If the absorbance spectrum of theacceptor ‘quencher’ (Ab-peptide) overlaps with the fluorescenceemission spectrum of the donor fluorophore [enzyme trypto-phan(s)] (Fig. 4) a decrease in donor emission along with anincrease in acceptor emission intensity occurs. If these ‘quencher– fluorophores’ have unique locations in the enzyme, it is possibleto measure distances or changes in distances ‘r’ between them(Takahashi et al., 2004). The efficiency of energy transfer is a quan-titative measure of the number of quanta that are transferred fromdonor to acceptor and may be determined from the fluorescenceintensity of a sample that contained only the donor and from a cor-responding sample that contained acceptor and a donor (Clegg,1995, 1996). Moreover, the use of FRET results from the strongdependence of the rate and efficiency of energy transfer on thesixth power of the distance ‘r’ between donor and acceptor (Sklaret al., 1977; Chen et al., 2003).
FRET studies (Padayachee and Whiteley, 2011, 2013a, 2013b)confirm that tryptophan residues within nNOS and/or PAD changetheir position in the presence of any bound Ab-peptide fragment.The analysis of the primary structure and active site of each sub-unit of nNOS [PDB ID:1OM4] reveals 13 tryptophan residues ofwhich six [Trp306, Trp421, Trp510, Trp625, Trp678 and Trp716] are nearthe surface. According to an indepth study (Padayachee, 2013)Trp716 is identified as the single Trp residue involved in fluores-cence quenching by the Ab-peptides. The normal arginine sub-strate binds in the active site about 2.35 nm from Trp716
(Fig. 4A). For Ab17–21, Ab25–29, Ab29–33 and Ab33–37 the distance ‘r’
Heme
Trp716
Tetrahydro-L-Biopterin
FRET
Aβ
ërí =2.8 ó 3.7 nm
her e
ophore
Heme
Trp716
Tetrahydro-L-Biopterin
FRET
Aβ
ërí =2.8 ó 3.7 nm
her e
ophore B
rahydro-biopterin in the active region. (A) Arginine substrate binds 2.35 nm from aorescence quencher Ab-peptide fragments binding 2.8–3.7 nm from Trp716.
28 C.G. Whiteley / Neurochemistry International 67 (2014) 23–31
lengthens to between 2.83 and 2.97 nm while for the pseudo-pep-tides Ab17–21r, Ab17–21p, Ab29–33r and Ab29–33p it extends to between3.08–3.74 nm (Fig. 4B). This overall increase in ‘r’, in fluorescentintensity and in transfer efficiency reflect a general increase in en-ergy of association for the pseudo-peptides with nNOS lendingsupporting rationale and evidence for the strategic position ofthe two phenylalanines [Phe19, Phe20] and isoleucines [Ile31, Ile32]as being critical for initial binding to the enzymes.
3.4. Thermodynamic analysis
The interactive forces between the bound Ab-amyloid peptidefragments and nNOS and/or PAD are also determined from temper-ature-dependent thermodynamic parameters – enthalpy (DH), en-tropy (DS) and Gibbs free energy (DG). Since these values are allpositive it shows that not only are hydrophobic forces in operationwhen the Ab-peptide fragments interact with nNOS but the inter-actions are non-spontaneous (Ross and Subramanian, 1981; Straz-za et al., 1985). The process of fibrillogenesis is supported by otherwork that requires partial unfolding of disordered proteins (Rochetand Lansbury, 2000) with large positive thermodynamicallyfavourable DS values. A complete thermodynamic analysis forthe interaction of Ab17–21r; Ab17–21p; Ab29–33r; Ab29–33p; Ab17–21;and Ab29–33 with nNOS indicates more of an influence by Phe19
and Phe20 to initiate fibrillogenesis than by Ile31 and Ile32 (Padaya-chee and Whiteley, 2013a,b).
4. Inhibiting/reversing fibrillogenesis
Any substance that inhibits or reverses the progression of ADrequires an understanding of the molecular causes underlyingthe neurodegenerative processes. In the fight against amyloid-re-lated disease (Estrada and Soto, 2007; Porat et al., 2006; Dolphinet al., 2008; Saengkhae et al., 2007; Thapa et al., 2011; Ferreiraet al., 2011; Harris, 2012) the literature overflows with reports
Aβ-peptidefragment monomer
Aβ-fibriAβ-monom
ëEnzymeínNOS or
PADII
Fig. 5. Scheme to represent enzyme catalyzed formation of Ab-fibrils from Ab-peptide frananoparticles.
on the development of small molecules as anti-aggregation andanti-amyloidogenic agents, including cucurmin (Wang et al.,2009; Ono et al., 2004; Yang et al., 2005; Orlando et al., 2012; Khanet al., 2013) and nanoparticles (Padayachee et al., 2013), It is be-yond the scope of the present review to give a thorough detailedanalysis of all of these except, with respect to nNOS, to mentionthe effect of nanoparticles.
4.1. Ag/Au nanoparticles
The size of Ag/Au nanoparticles allow their unique and remark-able properties to be exploited, not only to include anti-microbialactivity (MubarakAli et al., 2011; Lekshmi et al., 2012) but alsochanges to the biological activity of biomacromolecules especiallyfrom within the nanomedical fraternity (Wigginton et al., 2010; Sal-ma et al., 2011; Srivastava et al., 2011; Sennuga et al., 2012a, 2012b).
The addition of Ag- and/or Au-nanoparticles to Ab-fibrils, whichare generated by the action of nNOS on various amyloid peptidefragments, gives a dramatic decrease in fibril concentration (mea-sured by Th-T fluorescence) to nearly zero within 60 s (Padayacheeet al., 2013) (Fig. 5). Since the nanoparticles show no direct influ-ence on Th-T fluorescence per se, they must actually reverse theaggregation of the fibrils into individual oligomers or, indeed,monomers. Even altering the order of addition between nNOS,nanoparticles and Ab-peptide fragments (Padayachee et al., 2013)support the fact that the nanoparticles did not prevent fibrillogen-esis but reversed it. Other reports on the action of nanoparticleswith fibrils has met with inconclusive and indifferent findings(Fei and Perrett, 2009; Auer et al., 2009).
5. Mechanistic aspects
Prefibrillar oligomers (soluble Ab-peptides) are primary causa-tive agents of AD compared to insoluble Ab (fibrils) that are inertor protective (Glabe, 2006, 2008). It is known that Ab fibrils, via
ler
Ag/Au nanoparticle
Ag/Au nanoparticle-fibril/monomer complex
gment monomers and subsequent depletion of both fibrils and monomers by Ag/Au
C.G. Whiteley / Neurochemistry International 67 (2014) 23–31 29
nucleation, increase monomer concentration and speed up theirassembly into toxic oligomers (Iwata et al., 2000a).
The existence of a rapid elongation/growth phase and an equi-librium phase during the mechanism of fibrillogenesis points to-wards a nucleated-polymerization model for fibrillogenesis. PADand/or nNOS, in the presence of amyloid peptides, act as ‘chaper-ones’ on Ab-peptide assembly either by increasing the ‘seeds’ nec-essary for the nucleation step or by stimulating fibril elongationthereby forming fibrils through an Ab–enzyme complex. After freeAb monomers, in solution, are bound to an enzyme, formulating anucleus and initiating their aggregation they subsequently becomeentrapped and couple to the existing aggregated monomers, lead-ing to an elongated fibril. An ordered nucleus is formed only after alag phase and in a ‘supersaturated’ solution of fibrils that formfrom ‘seeds’ (initially present) which eventually exceed the criticalconcentration of amyloid peptide (Rochet and Lansbury, 2000; Caf-lisch and Pellarin, 2006). This effect is enhanced by micelles thatare in equilibrium with soluble Ab monomers and provide nucleifor new fibrils allowing further formation of fibrils with time(Hao et al., 2010; Sambasivam et al., 2011). Based on this model,and with an increase in the amount of fibrils, there are more mi-celles that remain in solution until a point of saturation. Oncethe aggregation process begins and a critical nucleus forms, thesoluble fibrils, detected by the Congo Red assay, now form insolu-ble fibrils and precipitate.
It is more effective to find agents that prevent the initial stagesof Ab nucleation rather than those that block Ab deposition. Anymolecule that targets the secondary pathway by binding to amy-loid fibrils or inhibiting their interaction with monomers will pre-vent the toxic formation of oligomers and their inherent toxicity(Cohen et al., 2013). Reversing fibril formation will, in turn, reverseoligomer formation and the use of nanoparticles as therapeuticagents to reverse the formation of fibrils is indeed an exciting pros-pect. According to the ‘corona effect’ (Lynch and Dawson, 2008;Lynch, 2007; Calzolai et al., 2010; Cedervall et al., 2007) the nano-particles are surrounded by the amyloid peptide molecules in vivo(Fig. 5) creating an intense hydrophobic environment around theparticle. This, effectively, depletes the concentration of monomericpeptides and does not allow any ‘lag’ time, nor prevent the forma-tion of critical nuclei for the initial association phase and, inevita-bly, prevent fibril initiation and elongation. The nanoparticlesirreversibly bind to (and deform) the initial ‘corona’ layer of en-zyme molecules leading to a totally different structure and func-tional behavior of the biomacromolecule.
The entire amyloidogenic pathway involving nNOS and/or PADand Ab-peptides occurs within the glial cells (astrocytes) in the brainand any selective enzyme inhibition will prevent the fibrillogenesisof amyloid peptides, thereby suppressing fibril dependent neuro-toxicity and slowing the progress of AD. The interaction of theseshort peptide motifs: the pentapeptide motif (Ab17–21) (Fig. 3) andthree individual glycine zipper motifs: Ab25–29; Ab29–33; Ab33–37
and the complete ‘triple’: glycine zipper: Ab25–37 with Ab monomersprevent their assembly into fibrils in vivo and prevent Ab neurotox-icity in cell culture (Glabe, 2008; Giordano et al., 2009). Researchsuggests that the total number of glycine zipper regions in an Ab isthe key determinant of toxicity and any aggregation inhibitors thattarget the G-XXX-G motif may be able to block amyloidosis All ofthese events are considered crucial in suppressing AD (Padayacheeet al., 2012, 2013; Padayachee and Whiteley, 2011, 2013a, 2013b;Iwata et al., 2000b; Jones and Mezzenga, 2012).
6. Concluding comments
By correlating the kinetic analysis, the Congo Red assay and theThioflavin-T fluorescence data for the affinity of several amyloid
peptide fragments with nNOS and/or PAD there is evidence to sup-port a two stage transition. The incubation of nNOS from the brainwith the Ab-peptides cause rapid inhibition (>90% within 5 min)followed by the generation of soluble fibrils (quantified by CongoRed) (80% within 30 min) that undergo further fibrillogenesis intoinsoluble fibrils (indicated by Thioflavin T fluorescence). As far asPAD is concerned these times are slightly slower with soluble fi-brils being formed within 24 h and becoming insoluble after120 h. The most prominent peptide fragments to undergo fibrillo-genesis are Ab17–21, Ab17–28, Ab25–29, Ab29–33 and Ab25–37 with theleast prominent being Ab32–35. Three scenarios need mention: theenzyme activities are restored completely meaning that the fibrilsdo not block the active sites; the rate of decrease in soluble fibrils ismirrored by the rate of formation of insoluble fibrils; all Ab-pep-tides, in the absence of enzyme, do not form fibrils.
Data reveal that nNOS has only one binding site and that itsfluorescence is quenched by the amyloid peptide supporting theformation of a nNOS–Ab-complex. Furthermore Trp716 becomesaccessible on binding of the Ab-peptides and according to FRETanalysis the distance between them varies between 2.8 and3.7 nm. The peptides interact with the enzyme with hydrophobicforces and in a non-spontaneous manner with the critical residuesresponsible for initiating not only inhibition of nNOS but in fibril-logenesis being identified as the two phenylalanine [Phe19, Phe20]and the two isoleucine [Ile31, Ile32] residues.
Ab monomers bind to nNOS and/or PADII to formulate a nucleusand initiate their aggregation with a subsequent extension to anexisting aggregated monomer, leading to an elongated fibril. Silverand gold nanoparticles effectively reverse fibrillogenesis by deplet-ing the concentration of amyloid peptide molecules in vivo andpreventing the formation of critical nuclei in the initial associationand fibril elongation.
Understanding the function and action of PADII and/or nNOS,with respect to the formation of senile plaques and amyloid pep-tide aggregation facilitates more of an understanding of neurode-generation. A case of taking ‘AME’ against Alzheimer disease.
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