A Peptide Hairpin Inhibitor of Amyloid β-Protein Oligomerization and Fibrillogenesis

Article (PDF Available)inBiochemistry 48(48):11329-31 · October 2009with102 Reads
DOI: 10.1021/bi901325g · Source: PubMed
  • 26.89 · University of California, San Diego
  • 33.87 · University of California, Los Angeles
  • 48.9 · University of California, Los Angeles
Abstract
Amyloid beta-protein (Abeta) self-assembly is linked strongly to Alzheimer's disease. We found that PP-Leu, a tridecapeptide analogue of broad-spectrum antiviral peptides termed theta-defensins, potently inhibits Abeta oligomer and fibril formation. This effect appeared to be mediated through sequestration of the amyloidogenic Abeta peptide in colloid-like assemblies. PP-Leu comprises a turn formed by a d-Pro-l-Pro amino acid dyad and stabilized by a disulfide bond, a motif that was exceptionally resistant to endoproteinase K digestion. This combination of assembly inhibitory activity and protease resistance suggests that PP-Leu may have potential therapeutic value.

Figures

pubs.acs.org/BiochemistryPublished on Web 10/30/2009
r
2009 American Chemical Society
Biochemistry 2009, 48, 11329–11331 11329
DOI: 10.1021/bi901325g
A Peptide Hairpin Inhibitor of Amyloid β-Protein Oligomerization and Fibrillogenesis
Ghiam Yamin,
‡,§,^,@
Piotr Ruchala,
)
and David B. Teplow*
,§,^,@
Medical Scientist Training Program,
§
Department of Neurology,
)
Division of Infectious Diseases, David Geffen School of Medicine
at UCLA;
^
Neuroscience Interdepartmental Ph.D. Program,
@
Molecular Biology Institute, Brain Research Institute,
Chemistry-Biology Interface Training Program, University of California, Los Angeles, California 90095
Received July 30, 2009; Revised Manuscript Received October 24, 2009
ABSTRACT:
Amyloid β-protein (Aβ) self-assembly is linked
strongly to Alzheimer’s disease. We found that PP-Leu, a
tridecapeptide analogue of broad-spectrum antiviral pep-
tides termed θ-defensins, potently inhibits Aβ oligomer
and fibril formation. This effect appeared to be mediated
through sequestration of the amyloidogenic Aβ peptide in
colloid-like assemblies. PP-Leu comprises a turn formed by
a
D
-Pro-
L
-Pro amino acid dyad and stabilized by a
disulfide bond, a motif that was exce ptionally resistant to
endoproteinase K digestion. This combination of assembly
inhibitory activity and protease resistance suggests that
PP-Leu may have potential therapeutic value.
Alzheimer’s disease (AD) affects an estimated 5.2 million
Americans and is the fifth-leading cause of death among those
over the age of 65 (1-3). AD is characterized by cerebral
extracellular amyloid fibril formation by the amyloid β-protein
(Aβ) and by intraneuronal paired helical filament formation by
the protein tau (3). Aβ exists predominately as a 40- or 42-amino
acid protein. Oligomerization and fibrillogenesis of Aβ are
thought to cause AD (4, 5). Effective inhibitors of Aβ assembly
thus have been sought (6-8).
Several groups have investigated the use of peptide and
peptidomimetic inhibitors (6-8). Soto et al. used small β-sheet
breaker” peptides that bind to Aβ and prevent its assembly into
toxic structures (7). Assembly inhibitors also have been produced
using short N-methyl peptides homologous to the central hydro-
phobic cluster region of Aβ,Leu
17
-Ala
21
, which is important in
Aβ fibril formation (8). Recently, Fradinger et al. (9) reported
the synthesis of peptide inhibitors designed from hydrophobic
C-terminal segments of Aβ. Common features of these inhibitors
are their hydrophobicity and their propensity to incorporate into
β-sheets. These characteristics also are displayed by potent
antiviral peptides, termed θ-defensins, and by peptidic analogues
of the toxin invariant domain of cholesterol-dependent cytoly-
sins (10, 11).
To determine whether θ-defensins or cytolysins might also be
active in inhibiting Aβ assembly, we used thioflavin T (ThT)
fluorescence to monitor the development of β-sheet structure in
mixtures of Aβ42 and each of 10 of these potential inhibitors
(data not shown). Nine of the inhibitors formed extended β-sheet
structures themselves, precluding their further use. However, one
compound, the θ-defensin analogue PP-Leu, was active and did
not display significant ThT binding (data not shown). PP-Leu
(Figure 1) is a 13-amino acid peptide hairpin stabilized by
aCys
2
-Cys
13
disulfide bond and a type II
0
β-turn formed by a
D
-Pro
7
-
L
-Pro
8
moiety (12). Such cyclic peptides can possess
exceptional structural stability and protease resistance, impor-
tant properties for maximizing biological activity and half-life
in vivo (13).
To explore the inhibitory effects of PP-Leu systematically, we
determined the concentration dependence of PP-Leu inhibition
of Aβ assembly. To do so, ThT fluorescence assays were
performed using freshly prepared, aggregate-free Aβ42 incubated
at 37 C(Figure2).Aβ42, the longer of the two predominant Aβ
isoforms in humans, is thought to be the key pathologic agent in
AD (3, 4). Aβ42 incubated alone exhibited a rapid increase in
ThT fluorescence that reached a plateau after 24 h and then
declined thereafter. This behavior is characteristic of amyloid
assembly reactions (14). PP-Leu diminished the rate of Aβ42
assembly, and the final level of ThT bound, in a concentration-
dependent manner. At 24 h, samples of PP-Leu and Aβ42 at
molar ratios of 1:5 and 1:1 yielded ThT signals that were
1
/
2
and
1
/
4
of that of Aβ42 alone, respectively. At 5:1 and 10:1 molar
ratios, no significant increase in ThT binding was observed over
time. No ThT signal increase was observed in these latter samples
even if the incubation was extended to 300 h (data not shown).
To determine whether PP-Leu blocked fibril formation, trans-
mission electron microscopy (TEM) was performed on aliquots
removed during ThT assays performed with PP-Leu and Aβ42 at
a 5:1 molar ratio (Aβ concentration of 55 μM). The ThT signal
remained constant (<25 fluorescence units, which is very low)
throughout the assay, demonstrating that insignificant β-sheet
formation occurred. Aβ42 incubated alone exhibited an 50%
increase in the magnitude of the ThT signal during the assay and
produced abundant amyloid fibrils (Figure 3a). These fibrils
display a twisted morphology, widths of 10 ( 1.8 nm, and lengths
approaching 1 μm. PP-Leu samples incubated alone produced a
mesh comprising both straight and curved assemblies with widths
of 4 ( 0.5 nm and lengths of 29 ( 6 nm (Figure 3b). Aβ42
incubated with PP-Leu produced a PP-Leu-like mesh (Figure 3c),
not the uniform surface of fibrils seen in the absence of
F
IGURE
1:
(a) Primary structure and (b) ball-and-stick model of PP-
Leu. Atoms are color-coded: C, gray; O, red; N, blue; S, yellow.
This work was supported by the UCLA Chemistry-Biology Interface
program (G.Y.), the Jim Easton Consortium for Alzheimer’s Drug
Discovery and Biomarkers at UCLA (D.B.T.), funds from the Adams
and Burnham endowments provided by the Dean’s Office of the David
Geffen School of Medicine at UCLA (P.R.), and National Institutes of
Health Grant AG027818 (D.B.T.).
*To whom correspondence should be addressed. E-mail: dteplow@
ucla.edu. Telephone: (310) 206-2030. Fax: (310) 206-1700.
11330 Biochemistry, Vol. 48, No. 48, 2009 Yamin et al.
PP-Leu (Figure 3a). The widths of the structures in this mesh
were 20 nm.
Monitoring the kinetics of increasing ThT fluorescence de-
monstrated that the midpoint of the conformational transition of
the disordered Aβ monomer to the assembled β-sheet-rich fibril
occurred at 11 h (Figure S1). To determine if PP-Leu blocked
fibril elongation, the compound was added to a fibril formation
system after 11 h. As seen in Figure S1, addition of PP-Leu at an
Aβ42:PP-Leu molar ratio of 1:5 resulted in an immediate and
significant diminution in fluorescence to levels indistinguishable
from those observed at the beginning of the experiment. This
decline occurred over a 3 h time period, after which fluorescence
remained relatively constant for 48 h before slowly declining
during the remaining 100 h of the incubation. In comparison,
addition of PP-Leu to Aβ42 at the same Aβ42:PP-Leu molar
ratio, but at the start of the experiment, produced a 50% lower
initial fluorescence, a smaller absolute increase in the magnitude
of the ThT signal during the first 24 h, and a declining signal
therafter. The final level of ThT fluorescence in samples in which
PP-Leu was added after initiation of fibril formation was higher
than that in samples in which PP-Leu was added before fibril
formation began. In the vehicle alone [5% (v/v) DMSO] control,
a small initial decrease in the magnitude of the ThT signal and a
smaller maximal ThT signal were observed relative to those of the
untreated control.
We next determined the effect of PP-Leu on Aβ42 oligomer-
ization by using photo-induced cross-linking of unmodified
proteins (PICUP) to rapidly and efficiently “freeze” metastable
Aβ oligomers in a state amenable for study by SDS-PAGE (15).
In the absence of cross-linking, Aβ42 displayed monomers and
trimers (Figure S2, lane 2) whereas PP-Leu was monomeric
(Figure S2, lane 3). The Aβ42 trimer band is an SDS-induced
artifact (15). Un-cross-linked mixtures of PP-Leu and Aβ42 at
molar ratios of 1:1 and 5:1 produced oligomer patterns indis-
tinguishable from that of un-cross-linked Aβ42 alone (Figure S2,
lanes 4 and 5). After cross-linking, Aβ42 produced an oligomer
distribution comprising monomers through octamers (Figure S2,
lane 6), with nodes at monomer and pentamer/hexamer
(paranuclei). Addition of PP-Leu to Aβ42 at a 1:1 molar ratio
inhibited paranucleus formation almost completely and caused a
very significant shift of the oligomer frequency distribution to
lower orders (e4) (Figure S2, lane 8). A 5-fold molar excess of
PP-Leu had a greater effect on Aβ42 oligomerization, blocking
oligomerization entirely and producing an oligomer distribution
similar to that of un-cross-linked Aβ42, but with even less trimer
(Figure S2, lane 9).
In theory, the inhibition of Aβ42 oligomerization could have
resulted from effects of PP-Leu on the PICUP chemistry itself. To
test this hypothesis, we assessed the cross-linking potential of the
irradiated cross-linking agents APS and Ru(bpy) incubated with
or without PP-Leu prior to their addition to Aβ-containing tubes
(Figure S3a). Preirradiation of APS and Ru(bpy) produced an
Aβ42 oligomer distribution ranging from monomer through
hexamer, with an increased population distribution toward
trimer and tetramer (Figure S3b, lane 1). Preirradiation of the
reagents in the presence of a 5-fold molar excess of PP-Leu
produced an oligomer size distribution that was indistinguishable
from that produced in the absence of PP-Leu (cf., Figure S3b,
lanes 1 and 2). Preirradiation of the cross-linking reagents,
followed by their addition to a PP-Leu/Aβ42 mixture [5:1 molar
ratio (Figure S3b, lane 3)], produced an oligomer size distribution
qualitatively similar to that produced in an equivalent cross-
linking reaction in which all reactants were irradiated together
(Figure S2, lane 9). These results thus do not support the
hypothesis but instead support the conclusion that PP-Leu does
indeed inhibit Aβ42 oligomerization.
Taken together, the data discussed thus far suggest that PP-
Leu may disrupt structures existent in growing fibrils, preventing
further assembly, or have a direct effect on incoming Aβ
monomer units that otherwise would bind to fibril ends. Several
amyloid inhibitors are known to form aggregates that inhibit
protein aggregation through sequestration within colloidal pha-
ses (16
). PP-Leu also forms non-amyloid aggregates (Figure 3b), a
property that may explain its mechanism of action. A sequestra-
tion mechanism has been reported in studies of the Parkinson’s
disease-associated protein R-synuclein (17). These studies showed
that the protein β-synuclein, like PP-Leu, formed nonfibrillar
assemblies that inhibited R-synuclein fibril formation. Impor-
tantly, β-synuclein coexpression in R-synuclein transgenic mice
alleviated motor deficits, neurodegeneration, and R-synuclein
accumulation (18). PP-Leu, like β-synuclein, thus may have
therapeutic potential.
Cyclic peptides have enhanced structural stability relative to
linear peptides, an important property with respect to biological
activity and stability in vivo. To determine formally whether PP-
Leu also exhibited enhanced stability, we compared the protease
sensitivity of PP-Leu in its native cyclic (disulfide) and linear
(disulfide reduced) forms. To do so, proteinase K (PK), a potent
nonspecific protease, was used to digest oxidized and reduced
forms of PP-Leu at 37 C at high (1:1) enzyme:substrate (E:S)
F
IGURE
2:
Thioflavin T (ThT) binding. Aβ42, at a concentration of
55 μM, was incubated at 37 C alone, with vehicle (DMSO), or with
PP-Leu. β-Sheet structure then was monitored using ThT. Fluore-
scence units (FU) are arbitrary.
F
IGURE
3:
Electron microscopy of (a) Aβ42, (b) PP-Leu, and (c) Aβ42
with PP-Leu. The scale bar is 100 nm.
Rapid Report Biochemistry, Vol. 48, No. 48, 2009 11331
ratios. Digestion of oxidized and reduced PP-Leu yielded peptide
fragments that were expected on the basis of the peptide cleavage
specificity of PK (Table 1), with the exception that an additional
peptide fragment, PP-Leu(3-11), was observed in the cleavage of
reduced PP-Leu. Protease digestion progress curves (Figure S7)
show that oxidized PP-Leu was digested rapidly and that reduced
PP-Leu was digested even more rapidly (digestion of the latter
peptide essentially was complete by 1 h). The normalized initial
digestion rate of oxidized PP-Leu was 10%/h, whereas that of
reduced PP-Leu was 88%/h, 9-fold higher (Figure S7, inset).
Aβ40 was used to assess the kinetics of proteolysis of a statistical
coil conformer, a conformer that should be substantially less
protease resistant than the structured PP-Leu peptide. We ob-
served almost complete Aβ40 digestion within 1 min (Figure S7),
a kinetics far more rapid than that of either reduced or oxidized
PP-Leu. These results show that native, cyclic PP-Leu displays
the increased protease resistance predicted for such peptides.
In conclusion, a 13-residue peptide hairpin, PP-Leu, blocks the
formation of the extended β-sheets necessary for Aβ fibril
growth, disrupts the structure of preformed fibrils, and potently
inhibits Aβ oligomerization. The mechanism of inhibition ap-
pears to be Aβ sequestration, as observed with β-synuclein
(17, 18)andnovelC-terminalAβ inhibitors (9). Importantly,
PP-Leu shows substantial protease resistance. Taken together,
these results suggest that PP-Leu may be of value as an AD
therapeutic.
ACKNOWLEDGMENT
We thank Dr. Mingfeng Yang for producing the ball-and-stick
model of PP-Leu, Mr. Eric Pang for assistance and insights with
the mass spectrometry data, Drs. Panchanan Maiti and Alan
Waring for technical insights, and Dr. Robert I. Lehrer for
helpful comments.
SUPPORTING INFORMATION AVAILABLE
Detailed experimental procedures, materials and methods, and
Figures S1-S7. This material is available free of charge via the
Internet at http://pubs.acs.org.
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Table
1: Proteinase K Digestion of Oxidized and Reduced PP-Leu
peptide
fragment
peptide
sequence
observed
mass
(oxidized)
a
mass error
(oxidized)
b
observed
mass
(reduced)
a
mass error
(reduced)
b
3-11 RLILPPLRL n.o.
c
n.o.
c
1112.6 0.2
5-11 ILPPLRL 844.1 0.0 843.3 -0.8
6-12 LPPLRLI 844.1 0.0 843.3 -0.8
6-11 LPPLRL 730.7 -0.2 730.7 -0.2
7-12 PPLRLI 730.7 -0.2 730.7 -0.2
7-11 PPLRL 596.6* 0.8 596.3* 0.5
5-9 ILPPL 574.5 -0.2 574.3 -0.4
a
Mass is for the singly sodiated [M þ Na
þ
]
þ
peptide fragment, except
where indicated by an asterisk, in which case the ion is the singly protonated
[M þ H
þ
]
þ
peptide fragment.
b
Observed average mass minus calculated
average mass. All exp eriments were performed in triplicate.
c
n.o. = not
observed.
    • "The aggregation of the Aβ peptide into oligomeric assemblies and ordered fibrils is associated with Alzheimer's disease (Chiti and Dobson 2006; Haass and Selkoe 2007; Knowles et al. 2014). For this reason, this peptide has been the subject of intense research and an increasing number of small molecules have been reported to interfere with its aggregation process (Necula et al. 2007; McKoy et al. 2012; Hawkes et al. 2009; Porat et al. 2006; Wang et al. 2014; Yamin et al. 2009 ). The existence of various metastable structures of this peptide, however, poses tremendous challenges in developing strategies to avoid its aggregation. "
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