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International Journal of Neuroscience
ISSN: 0020-7454 (Print) 1543-5245 (Online) Journal homepage: http://www.tandfonline.com/loi/ines20
Functional Amyloids: Interrelationship with other
Amyloids and Therapeutic Assessment to Treat
Neurodegenerative Diseases
Sutapa Som Chaudhury & Chitrangada Das Mukhopadhyay
To cite this article: Sutapa Som Chaudhury & Chitrangada Das Mukhopadhyay (2017):
Functional Amyloids: Interrelationship with other Amyloids and Therapeutic Assessment
to Treat Neurodegenerative Diseases, International Journal of Neuroscience, DOI:
10.1080/00207454.2017.1398153
To link to this article: http://dx.doi.org/10.1080/00207454.2017.1398153
Accepted author version posted online: 27
Oct 2017.
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Download by: [University of Florida]
Date: 28 October 2017, At: 05:01
Publisher: Taylor & Francis
Journal: International Journal of Neuroscience
DOI: https://doi.org/10.1080/00207454.2017.1398153
Functional Amyloids: Interrelationship with other Amyloids and Therapeutic
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Assessment to Treat Neurodegenerative Diseases
Sutapa Som Chaudhury1, Chitrangada Das Mukhopadhyay1*
1
Centre for Healthcare Science and Technology, Indian Institute of Engineering Science and
Technology, Shibpur, PO: Botanic Garden, Dist: Howrah- 711103, West Bengal, India.
*Address Correspondence to:
Dr. Chitrangada Das Mukhopadhayay, Centre for Healthcare Science and Technology, Indian
Institute of Engineering Science and Technology, Shibpur, PO: Botanic Garden, Dist: Howrah711103, West Bengal, India.
Tel: 91-9836544110; 91-9038510873
Fax: (033) 2668-2916
Email: *chitrangadam@chest.iiests.ac.in; somchaudhurysutapa@gmail.com
Functional Amyloids: Interrelationship with other Amyloids and Therapeutic
Assessment to Treat Neurodegenerative Diseases
Abstract:
Misfolded β-sheet structures of proteins leading to neurodegenerative diseases like Alzheimer’s (AD) and
Parkinson’s diseases (PD) are in the spotlight since long. However, not much was known about the
functional amyloids till the last decade. Researchers have become increasingly more concerned with the
degree of involvement of these functional amyloids in human physiology. Interestingly, it has been found
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that the human body is exposed to a tremendous systemic amyloid burden, especially, during aging.
Though many findings regarding these functional amyloids come up every day, some questions still
remain unanswered like do these functional amyloids directly involve in the fibrillization of Amyloid
beta (Aβ) 42 peptide or enhance the Aβ42 aggregation rate; whether functional bacterial amyloids
(FuBA) co-localize with the senile plaques of AD or not. A detailed review of the latest status regarding
the interrelationship between functional amyloids, pathogenic amyloids and misfolded prions and
therapeutic assessment of functional amyloids for the treatment of neurodegenerative diseases can help
identify an alternative medication for neurodegeneration. A unique mathematical model is proposed here
for alteration of Aβ42 aggregation kinetics in AD to carve out the future direction of therapeutic
consideration.
Keywords: Amyloid beta; FuBA; amyloid-burden; mathematical modeling; In-silico model.
Introduction:
Amyloids are insoluble, proteinaceous and fibrillar cross-β-sheet quaternary structures [1] and
amyloidogenesis refers to the aggregation of peptides leading to the synthesis of these amyloids
[2]. Aβ 1-42 has been usually considered as one of the hallmarks of AD pathogenesis, but
recently growing evidence has indicated that a group of amyloids, namely functional amyloids,
may also be associated with normal physiological functions of bacteria to mammals. Functional
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amyloids play a diverse role, ranging from biofilm formation, development of aerial structures to
the regulation of melanin synthesis, scaffolding, epigenetic control, transfer of information and
so on [3]. Both the amyloids are highly resistant to proteolysis and most of them are selfreplicating. Functional amyloids are not harmful to their host, rather play vital roles, e.g., an
amyloid protein activates the Clotting factor XII and helps maintaining hemostasis [4]; human
Pmel17 helps in melanin pigment biosynthesis [5]. The residential bacteria in the human
gastrointestinal (GI) tract produce amyloids that are functional and helpful for their survival in
the host [6]. The gut microbiota play important physiological functions for maintaining
homeostasis in the host body [7,8] and contribute to the proper integrity of the Blood Brain
Barrier (BBB) [9,10].
However, it has been found in recent studies that the human body is exposed to a
tremendous systemic amyloid burden due to the functional amyloid production ability of those
residential bacteria of humans; especially during the ageing-based reorganization of the epithelial
layer of the GI tract and the BBB [11]. Again, Aβ 40 induced increased permeability of BBB
enhance the risk factors in the pathophysiology of AD [12].
All these findings have raised questions whether these functional amyloids co-localize
with the characteristic fibrillar senile plaque of AD or by altering the kinetics of fibrillar
aggregation, functional amyloids worsen the disease condition in neurodegeneration. The whole
scenario becomes more complicated if we consider pathogenic prion protein PrPSc in the same
premise, as it is also a β-amyloid structure and has resemblance with Aβ of AD [13].
Current Food and Drug Administration of USA approved medications for AD are cholinesterase
inhibitors and memantine [14], which offer modest symptomatic improvement only. A partial βsecretase enzyme blocker is now in the center of attraction [15].
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A better understanding of structure function relationship and biogenesis of a diverse kind
of amyloids may lead to the discovery of a novel therapeutic for Alzheimer’s and similar
neurodegenerative diseases.
Structure-function-biogenetic relationship of amyloids:
Structural similarities:
Functional as well as pathogenic amyloids though vary in amino acid sequence, (Table 1)
possess a filamentous and un-branched cross-β-sheet conserved quaternary structure [16-18].
Solid state NMR and PITHIRDS-CT recoupling methods showed that the parallel in-register βsheet topology is omnipresent in pathogenic amyloid structure and also in functional amyloids
like Ure2, Sup35, Rnq1, the RPT domain of functional amyloid Pmel17, [19-21] and so on; with
an exception of Aβ40 (generated in vitro) which is an anti-parallel β-sheet [22]. These parallel
or anti-parallel cross β-sheet structures are employed as low energy structural fold [23] or as a
variant to avoid different strains, a phenomenon common in prions [24, 25].
Generally, the neurodegenerative disease associated pathogenic amyloids may accord
structurally [26] being in the same group. Even FuBA, e.g., HET-s also shows structural
similarity with pathogenic prions having a ‘prion forming domain’ (PFD) at its C-terminus [27].
Functional similarities:
Functional amyloids possess not only a diversified range of occurrence (Table 1) but also serves
in different biological systems, playing crucial roles from biofilm formation to storage vehicles
on the mammalian endocrine system [28]. Whereas, pathogenic amyloids like Aβ42 and PrPSc
are only recruited to hamper the normal physiological functioning [29]. Although, some
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functional similarities between these two types of amyloids bring them on a common platform.
HET-s in Podospora anserine regulates the fungal cell death pathway, namely ‘heterokaryon
incompatibility’ [30], but gets transmitted horizontally from one strain to another just like
infectious prion proteins. Thus, unlikely the structural FuBA – Curli fibers, fungal functional
protein HET-s mimics both prions and amyloidogenesis by transmitting as pathogenic prions and
forming amyloid aggregates [31,32].
The RIP homotypic interaction motif (RHIM) of Receptor interacting kinase 1 (RIP1) and
Receptor interacting kinase 3 (RIP3) (components of necroptosis signaling in mammals),
mediating assembly of these kinases into the amyloid fibrils found to be related to the PFD of
HET-s [33].
URE3 and PSI (yeast prion) also showed corresponds to the prion form of URE2p and Sup35p
(FuBA of Saccharomyces cerevisiae), which are normally soluble proteins, but aggregate in vivo
upon conversion to the prion state [21].
Structural FuBA differs from pathogenic amyloids in terms of biogenesis:
FuBA e.g., Curli fibers of E. coli are synthesized very much similar as the biogenesis of bacterial
flagella [34]. Just as flagellin subunits travel through the flagellar ‘MSP’ ring and attach to the
external end of that ring [35], CsgA secretes out of the cell along with CsgB and CsgF after
transcription from operons - csgDEFG & csgBAC [36]; and get fibrillated with the aid of CsgB
nucleus [37,38]. CsgG pore being an un-gated channel [39] drives the translocation of curli
subunits via the energetics of amyloid subunit folding [40]. Similarly, Chaplin proteins of
Streptomyces coelicolor (ChpA-H) secrete out of the cell and form insoluble layer of 4-6 nm
wide fibrils at air-water interface [41,42] around which all eight Chp proteins generate a bi-
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layered outer coat [43] and help dispersion of spores in wind [44] (Figure 1A and 1B).
Biogenesis of all neurodegenerative amyloids follows almost a common mechanism, in a holistic
way, i.e. the generation of a misfolded protein or peptide which acts as a nucleus to start a chainpolymerization of continuously producing mutated protein units. For AD this nucleating peptide
is the Aβ1-42 [45-47] (Figure 2), in Parkinson’s (PD) this is the α-synuclein [16,48], in
Huntington’s disease this nucleating peptide is the mutated Htt [17,49] and in prion disease, it is
the infectious PrPSc [50] with an additional property to transmit between diseased and healthy
individual [51] (Figure 3).
Harmony in the mechanism of action:
As discussed above, biosynthesis of the senile plaques in AD and in prion diseases show a
synchrony, being more or less similar type of chain elongation reaction. Fascinatingly, fungalfunctional amyloid namely, HET-s imitates a chain elongation reaction like the prion proteins.
The infectious HET-s with the aid of its PFD draws more and more incompatible HET-S and
form fibrillar aggregates [52].
A brief comparison between functional amyloids and pathogenic amyloids is given in Table 2.
Coexistence of Functional and pathogenic amyloids in the human system and its
implications:
The structural, functional similarities, as well as the mode of action of different amyloids,
indicate that, if FuBA e.g., Curli, Hydrophobins, increases over time in the GI tract or in another
part of the human body, it will burden the load of similar kind of amyloids in the body. The
indirect effect of bacterial amyloid/endotoxins on CNS mitochondria due to molecular mimicry
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[53] also supports this claim [54,55]. But the question is whether or not the presence of
pathogenic Aβ42 or other neurodegenerative amyloids and the FuBA in the human body at the
same time is just a coincidence. Moreover, it is of great concern if these functional amyloids get
deposited in liver, kidney, colon or any other body parts of human beings [56]. The mechanisms
by which these different types of amyloid are cleared out of the human body, the evolutionary
impact of these functional amyloids in relation with the pathogenic amyloids like Aβ42 and
PrPSc are important areas of ongoing research.
Deposition of FuBA in our body:
Aβ42 peptide and other amyloids are characterized and subsequently defined by amyloid
deposits and non-functioning of a particular organ or total system [57]. In systemic amyloidosis,
amyloidogenic precursor proteins are synthesized at distinct sites from the site of amyloid
deposition [58] and for localized one, the site of amyloidogenic precursor protein synthesis and
deposition are the same [58,59].
Our concern here is whether these FuBA are increasing the burden of amyloid deposition
in the brain with Aβ42, i.e. whether these bacterial amyloids are involved in systemic amyloid
disease. This can be hypothesized that, if FuBAs are involved in systemic amyloidosis, they
would come into the CSF and brain via the circulation and burden the amyloid-load.
Curli, hydrophobins, and gut associated FuBAs might be directly associated with the
breakout of the symptoms of gastrointestinal-amyloidosis [60,61]. The immuno-histochemical
analysis with tissue samples from the patients as well as from a control subject might give an
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answer to this.
FuBA and its impact on Blood-Brain-Barrier permeability:
FuBA may cross the BBB and get full access in the brain hypothalamus if situation favors such
as recurrence of a leaky BBB, altered pattern of gut endothelia and so on. Practically, advanced
stage of AD itself may favor the entry of FuBA in brain interior; as Aβ 1-40 via activation of
JNK/p38 MAPK pathway induces an increase in BBB-permeability [62]. Mutually, the increased
TNFα from uplifting gut microbiota during aging and different cytokines from activated
leukocytes and CNS resident cells in advanced AD exhibit induction of altered paracellular flux
of BBB [63,64]. This results in a reorientation of tight junction protein ‘Occludin’ in a
concentration dependent manner, leading to caspase 3/7 induced apoptosis of brain endothelial
cells [64]. Though there is no direct evidence present for the FuBA to cross the BBB Zipser and
colleagues found significant prothrombin leakage from blood to the CNS in advanced AD
patients as a proof of altered BBB [65]. Increased CSF/plasma protein ratio of albumin and IgG
in AD patients also reflects a leaky BBB [66]. Even much earlier, it was evidenced that; soluble,
circulatory Aβ can cross the BBB and may contribute to the parenchymal amyloid beta
deposition in AD [67]. Thus, in the case of impaired permeability of BBB, FuBA may get an
uncontrolled access in the brain-parenchyma.
Clearance of amyloids from the human system:
Fibrillar β-amyloids, as well as FuBAs, are phagocytosed through the interaction with microglia
[68,69], following cytokines and Reactive Oxygen Species (ROS) generation [70]. The
triggering receptors expressed in myeloid/microglial cells-2 (TREM2) along with membranespanning linker protein TYROBP (DAP12) are employed to phagocytose Aβ40 and Aβ42
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monomeric peptides [71,72].
Complicating the situation bacterial LPS behaves as pro-inflammatory neurotoxins and
down regulates TREM2 and subsequent phagocytosis of monomeric amyloid debris [73].
Talking about infectious prions, after getting access via the M-cells in Peyer’s patch PrPSc
are encountered by the epithelial TLRs [74] and activates microglial cells in the CNS following
priming by astrocytes and even directly binds C1q and factor-H [75]. Once activated, microglial
cells do over-express TLR2, TLR4, and miR146a and up-regulate various markers like TREM2,
SiglecF, CD200R and FCγ receptors in non-classical immune response [76]. After proper
activation, microglia in a similar way as do in AD, activate MHC-II and CR3 receptors, leading
to release of pro-inflammatory cytokines like different interleukins (IL) - IL-1, IL-6, IL-12, and
anti-inflammatory cytokines like IL-4, IL-10, and IL-13 & TGF-β later on [77].
Inhibition of proteasomal degradation by pathogenic amyloids:
In Alzheimer, even 1µM concentration of Aβ42 oligomers suppresses the proteasomal activity
by acting as a competitive inhibitor of the proteolytic subunit of h20S proteasome [78]. This
suggests that Aβ42 oligomers are subjected to h20S proteasomal clearance beside microglial
phagocytosis, though hamper the clearance of other ubiquitin conjugated non-functional proteins
and lead to intra-neuronal deposition of those junk proteins.
The down-regulation of ubiquitin conjugate clearance, i.e. the normal proteasomal
activity is also associated with PD [79], Huntington’s disease [80] and amyotrophic lateral
sclerosis (ALS) [81].
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The Evolutionary link between functional and pathogenic amyloids:
The assessment of the evolutionary link between functional and pathogenic amyloids must be
resolved in determining the interrelationship between these two types of amyloids.
A direct relation between amyloids with similar functions is recognized; e.g, RHIM and
HET-S motifs both serving cell necroptosis are thought to be evolutionarily related [82,83]. On
the other hand, having a C-terminal PFD, HET-s protein shows structural similarity with prions
but differ functionally [84].
Now talking about the evolutionary selection pressure of amyloids we can predict that, if
functional amyloids are under positive evolutionary selection pressure playing an advantageous
role in many organisms; then Aβ42 fibrils, pathogenic prion - PrPSc, α-synuclein and mutant Htt
should be under negative selection pressure serving disadvantageously in the human being.
Instead, researchers argued that Aβ is, in fact, neuroprotective; e.g., Aβ fibrils and plaques sink
down the toxic oligomers or wall off toxic Aβ oligomers [85] and hence prevent formation of
Aβ-oligomer-generated membrane destroying pores and/or subsequent redox reactions [86]. Here
comes the new concept that amyloid structures lie outside the constraints of evolutionary
pressure as these fibrils have not evolved through random DNA mutation rather via physical
interactions and protein folding [87,18]. This implies that there is no conserved primary amino
acid sequence selected through the evolutionary process, to correlate with the conserved
quaternary amyloid structures. Only the forces of protein folding are the deciding factors for
these stable quaternary conformations of any protein.
Carving the way for the improvement of pharmacological therapeutics:
A Mathematical model to determine any alteration in Aβ42 aggregation kinetics:
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A mathematical model proposed combining a bivariate equation and Weibull function as a
chemical concentration model [88] can be used to evaluate the alteration (if any) in the kinetics
of Aβ42 aggregation in the presence of a FuBA at a particular concentration. This equation has
been successfully applied to evaluate the inhibitory effect of organic acids [89] and metals [90]
on the growth of bacteria and the inhibitory effects of some chemical compounds on fibril
aggregation kinetics e.g., inhibitory effect of epigallocatechin-3- gallate on in vitro aggregation
of synthetic insulin [91], the inhibitory effect of mono and Bi flavonoids on Aβ42 amyloid
protein of Alzheimer’s disease [91] and so on. Here, we propose to evaluate the equation for the
analysis of change in the rate of Aβ42 fibril aggregation in the presence of functional amyloid(s);
where the inhibitory compounds of previous studies will be replaced by the functional amyloid.
The data which would be analyzed by this mathematical equation could be obtained by
performing an in vitro experiment where the aggregation rate of Aβ42 in the presence of a FuBA
(synthetic) at a particular concentration and conformation would be measured by ThT
fluorescence [91] intensity at an excitation wavelength of 450 nm and an emission wavelength
range of 460 nm to 520 nm. The mathematical equation is as follows:
X= Xm. / [1+ exp{2+(4vm. (λ.-t)/Xm.)}]
Where:
Xm. = Xm {1-Kx [1-exp (-ln2 (C/mx)^ax)]}
vm. = vm {1-Kv [1-exp (-ln2 (C/mv)^av)]}
. =  {1+K [1-exp (-ln2 (C/m)^a)]}
Where Xm is the aggregation growth at its maximum limit, vm is the maximum
aggregation rate, λ is the lag phase and C is the concentration of FuBA with a particular
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conformation. The meanings of other symbols and their corresponding units are summarized in
Table 3. The dependent variable of response or time dependent signal (X) is to detect amyloid
protein aggregation by ThT fluorescence intensity at 460 nm to 520 nm in the in vitro assay. It is
to be noted that, different FuBA, other than that of GI tract when present in vivo may contribute
to the rate of aggregation of Aβ42 fibrils; in such case, this equation might follow an exponential
logarithm and the final kinetic equation would be changed according to the respective variable
function(s).
Development of an in silico model to predict colocalization of pathogenic and nonpathogenic
amyloids in the human system:
It can be hypothesized that to alter the kinetics of Aβ42 fibrillization, gut microflora derived
FuBA would employ a co-localization mechanism. To provide evidence, beside the classical
Immuno-histochemical double labeling experiments [92] one new-age scientific approach will be
to generate an in silico model. In this computer modeling [93] a vast sample data from AD
patients would be analyzed, followed by wet lab experimental validation through latest
molecular biological techniques.
Similarly, Immune-precipitation of blood and CSF samples from AD patients with
primary antibodies [94] against the functional amyloids would not be sufficient to confirm the
increase of amyloid burden with age; because other variable parameters like the physiological
condition of the gut, the presence of other kinds of amyloids are to be analyzed at the same time.
This can only be done with an in silico model supplemented with the immense data from AD
patients.
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Such a clinical trial simulation tool has been developed with the aid of a standard
database, model development, and evaluation, and was approved by FDA and EMA in 2013
[95]. This was proved to be helpful for the detection of disease progression based on a
longitudinal AD assessment scale-cognitive sub-scale scores, as well as beneficial for the clinical
phase trials for drug evaluation and appeared stretchier than final phase trials of Alzheimer’s
drugs, considering the different non-linear effects shown by the drugs [95].
Throwing light on future therapeutics:
Treatment with functional amyloid against β-amyloid:
When it is of concern whether FuBA enhances pro-inflammatory responses in neurodegeneration
it comes as a surprise that, FuBA like Curli can act as an immuno-modulator elevating antiinflammatory IL10 level via TLR2 activation when only gut epithelia are impaired but strictly
not in the case of an intact gut epithelial barrier [10]. Oppong and colleagues showed that, when
Curli fibers were introduced through intraperitoneal injection and allowed to interact directly
with gut lamina propia, the expression level of IL10 got increased [10]. The reason behind this
may be some alteration in the activation of the adapter molecule MYD88 or TIRAP/MAL
leading to switching from the downstream severe pro-inflammatory pathway to healing antiinflammatory response [96]. Thus, if Curli fibers were targeted to the CNS with the aid of tagged
nano-particles [97] increased level of anti-inflammatory IL10 may help to switch M2 microglial
phenotype from pro-inflammatory phenotype M1 [98] and thus help reduce neuroinflammation.
In fact, IL4 and IL10 treatment have been tested in vitro and in vivo and proved to improve
pivotal neuroinflammation in AD [99,100].
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Inhibition of Necrosome and inflammasome:
Pro-inflammatory cytokines particularly TNFα induced necroptosis and subsequent loss of a
subset of neurons in case of increased amyloid burden are the major pathogenesis of
neurodegenerative diseases [101]. Necroptosis, a programmed necrosis mediated by necrosome
complex [102,101] gets activated via the de-ubiquitination of RIP1 by Cylindromatosis (CYLD)
[103]. Reportedly, targeted inhibition of RIP1 kinase by necrostatin-1 has shown to give
protection from neuronal damage in animal models of brain injury, stroke and ALS [104,105].
Importantly, necrosome complex formation via RHIM domain interaction between RIP1 and
RIP3 leads to β-amyloid like complex formation [33] as a part of this necrosome complex and
thus targeted inhibition of RIP1 or RIP3 would be an indirect approach of treating β-amyloidosis
like AD, targeting other β-amyloid than Aβ42 directly. Similarly, the NLRP3 inflammasome
complex that serves a necrotic function in mammals via pro-inflammatory cytokines IL1β and
IL18 response [106] is reported to get activated by all kinds of amyloids including Aβ, serum
amyloid A, islet amyloid peptide, prions and functional amyloid – Curli [107,108]. Therefore,
hanging up the NLRP3 inflammasome particularly at IL1β signaling level using an IL1 receptor
antagonist, may result in the reduction of the pro-inflammatory pathogenesis of AD.
Controlled inhibition of JNK/ P38 MAPK pathway:
In brain diseases, cancer, rheumatoid arthritis and such many more diseases JNK/p38MAPK
pathway is being talked about and explained as a good therapeutic target since decades. It was
reported that p38MAPK inhibition can reverse the effect of Aβ42 induced boost in TNFα and
IL-1β level and subsequent synaptic dysfunction in mice-hippocampus [109], but the mechanism
was not known. Later on, in 2010, it was revealed that, scrambled Aβ peptide induced increase in
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cytokines triggers JNK/p38MAPK signaling pathway that leads to apoptosis of brain endothelial
cells (BEC) and consequent reorganization of BBB’s tight junction protein Occludin [62]. Also,
Lopez-Ramirez and colleagues mentioned the inhibition of the JNK pathway as a therapeutic
measure of BBB breakdown, adding the role of caspases 3/7 and caspase 9 in BBB impairment
[64].
Thereby, talking about the dual presence of Aβ42 as well as FuBA simultaneously in a
patient, JNK/p38MAPK pathway and/or caspase 3/7/9 seems to be an appropriate therapeutic
target to treat the critical neuroinflammatory condition.
The Role of Chaperones:
This is only the copious chaperone molecules which congregate all the neurodegenerative
diseases including AD, PD and prion diseases at a common terminus.
Evans and colleagues earlier reported that recombinant Hsp70/40 and Hsp90 chaperone
molecules block Aβ self-assembly causing structural changes in oligomers but remain unaffected
against fibrils [110].
Hsp70/Ssa3 isoform (Ssa1-4 are four cytosolic Hsp isoforms in S. cerevisiae) lowers αsynuclein-toxicity in PD via modulating autophagy [111] and Hsp90 binds and prevents the
aggregation of α-synuclein oligomers in an ATP-independent manner [112].
For mammalian prion diseases, Hsp70 either promotes degradation of PrPSc conformers
or protects against PrP-neurotoxicity [113]. Also, an up-regulation of Hsp90 was observed
previously in murine models of Bovine Spongiform Encephalopathies (BSE) [114].
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Interestingly, the role of Hsp70 and Hsp90 is eminent not only in mammalian pathogenic
amyloids but also in FuBA e.g., in yeast prion propagation. A current report in this field has
stated that the C-terminal MEEVD pentapeptide motif of Hsp90 is indispensable for URE3 prion
stability of S. cerevisiae [115] (URE3 is a prion form of native protein URE2).
Taking into account the diversified role of Hsp70-Hsp90 in the response of amyloids, this
Hsp70-Hsp90 dual machinery might be targeted for combination therapeutics against prion and
Aβ42 and/or prion, FuBA, and Aβ42.
Restoring proteasomal activity by pyrazolone containing small molecules or proteasome
activator and/or de-ubiquitinating enzyme inhibitor:
As discussed above, competitive inhibition of 20S proteasome by Aβ42, α-synuclein and mutant
Htt in AD, PD and Huntington’s disease respectively leads to accumulation of ubiquitin
conjugates in neurons. Thereby, small molecules that act as the activator of proteasomal complex
and increase the turnover rate of proteasome could be a therapeutic measure. Pyrazolone small
molecules were shown to enhance proteasomal activity and significantly attenuate disease
progression in the case of ALS [81]. An in vitro enhanced clearance of mutated Htt was reported
by over-expressing proteasome activator subunit PA28γ [116]. Also, the molecules that inhibit
USP14, a proteasome associated de-ubiquitinating enzyme can activate proteasomal degradation
[117] and thus can be another therapeutic target.
Vagotomy – a therapeutic approach for FuBA affected neurodegeneration:
PD is hypothesized to start in the GI tract and spread to the brain through the vagus nerve [118].
Recently, the presence of Lewy body in the GI tract of PD patients prior to their motor neuron
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dysfunction was detected [119]. Also, Helicobacter pylori infection in the stomach has been
proven to worsen the motor problems in PD [120]. Vagotomy i.e. a complete cutoff of vagus
nerve was proved to be a successful therapeutic measure in experimental volunteers suffering
from PD [118].
Here in this review, as we are assessing the role of FuBA of gut microbes in AD,
vagotomy can be a promising therapeutic target. We are to detect whether vagotomy can prevent
the enhancement of Aβ fibrillization kinetic in presence of FuBA.
Concluding Remarks:
The amyloid proteins in the neurodegenerative disease like Alzheimer’s (Aβ42) drew the
attention of researchers since long as compared to the widespread functional amyloids; but it is
not a truthful idea that amyloids are always associated with diseases; rather it can be allied with
function or disease. The functional amyloid of gut microflora may enhance inflammatory
symptoms and subsequent disease progression of Alzheimer’s. Here in this review, we have tried
to portray the pathophysiology of AD in presence of FuBA and increased amyloid burden; figure
out the factors that may favor this dual presence of Aβ and FuBA in the brain hypothalamus. As,
for example, increased level of TNFα during sepsis increases the permeability of the BBB and
even Aβ40 itself down-regulate the tight junction protein ‘Occludin’ of the BBB and thus make
the BBB more permeable. If such dual presence of Aβ42 and FuBA (and/or prion) had arisen,
this would affect the downstream clearance of Aβ42 oligomers/monomers in Alzheimer patients.
Aβ fibers generated by the oligomerization of Aβ42 monomers are cleared out by Toll Like
Receptor 2 (TLR2) signaling pathway. The downstream redox reactions producing ROS and proinflammatory cytokines are mainly responsible for the inflammation and symptomatic
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neurodegeneration in Alzheimer’s disease. Moreover, the ROS generated in TLR2 signaling
pathway down-regulate the Aβ42 monomer clearance via TREM2, and ultimately facilitates
senile plaque formation in AD. The whole scenario could be more complicated and might even
do so with the increase of amyloid load in our system with age through the influence of FuBA in
gut microflora. Bacterial LPS and FuBA allegedly down-regulate TREM2 robustly and therefore
the phagocytic clearance of monomeric amyloid debris (Figure 2).
Though we are still left with the answer whether these FuBA could cross the blood brain
barrier; with the aid of tracer 70 KD FITC-dextran it has been shown that Aβ40 can induce a
marked increase in hCMEC/D3 cell (BBB model) permeability via activation of JNK/p38
MAPK pathway, when incubated with scrambled Aβ40 peptide at a non-cytotoxic dose [62].
This, in turn, may dig the path for the entry of FuBA in the hypothalamus, crossing the BBB.
Interestingly, besides these negative roles of FuBA during aging, FuBA specifically Curli from
gut microflora can act as an immunomodulator in hapten (TNBS) induced colitis in experimental
mice models but not in the case of intact gut epithelial barrier [10]. Even, a crosstalk between gut
microbiota and the brain started during gestation, leads to the proper expression of tight junction
protein of the BBB and therefore the subsequent development of an intact and functional bloodbrain-barrier [9]. Thus, whether these FuBA would behave as immunomodulator or chronic
neuroinflammatory response developer is a dependent function of physiological background, i.e.
the status of gut epithelia, the presence of FuBA in the brain and beyond the gut, increasing
amyloid burden with age etc. and is subjected to estimation by in silico modeling.
Functional amyloids hence call more concern in pharmacological investigations of
neurodegenerative diseases. Establishment of an alternative medication of neurodegenerative
diseases nowadays in the center of attraction as the current symptomatic treatment is already
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ringing a bell of alarm.
The points discussed in this review article regarding treatment with functional amyloid
against β-amyloid, inhibition of necrosome, inflammasome and vagotomy can be helpful in this
aspect. A combination of the therapies proposed here may appear as a successful new age
alternative medication for neurodegeneration, after passing clinical phase trials.
Validation of the mathematical model and other experimental methods discussed above
will shed light on the unrevealed field of amyloid beta fibrillization kinetics in presence of
FuBA.
Conflicts of Interest:
The authors report no conflict of interest.
Funding:
This research did not receive any specific grant from funding agencies in the public, commercial,
or not-for-profit sectors.
Acknowledgements:
We thank Mr. Bhuban Ruidas (Indian Institute of Engineering Science and Technology, Shibpur)
for proof reading the manuscript and for his valuable suggestions.
Authorship Contributions:
Wrote or contributed to the writing of the manuscript: Som Chaudhury, Das Mukhopadhayay.
Graphics and drawings: Som Chaudhury.
Math model hypothesis proposed: Som Chaudhury.
Downloaded by [University of Florida] at 05:01 28 October 2017
Math model hypothesis evaluated: Das Mukhopadhayay.
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[135] Zhang J, Ke KF, Liu Z, et al. Th17 Cell-Mediated Neuroinflammation Is Involved in
Neurodegeneration of Aβ 1-42-Induced Alzheimer’s Disease Model Rats. PLoS One.
2013;8(10):e75786.
[136] Thackray AM, McKenzie AN, Klein MA, et al. Accelerated prion disease in the absence of
interleukin-10. J Virol. 2004;78(24):13697-13707.
[137] Hamilton JA, Whitty G, White AR, et al. Alzheimer’s disease amyloid beta and prion
protein amyloidogenic peptides promote macrophage survival, DNA synthesis and enhanced
proliferative response to CSF-1 (M-CSF). Brain Res. 2002;940(1):49-54.
[138] Nordstedt C, Näslund J, Tjernberg LO, et al. The Alzheimer A beta peptide develops
protease resistance in association with its polymerization into fibrils. J Biol Chem.
1994;269(49):30773-30776.
[139] Sitaras C, Naghavi M, Herrington MB. Sodium dodecyl sulfate–agarose gel
electrophoresis for the detection and isolation of amyloid curli fibers. Anal Biochem.
2011;408(2):328-331.
[140] Jendroska K, Heinzel FP, Torchia M, et al. Proteinase‐resistant prion protein accumulation
in Syrian hamster brain correlates with regional pathology and scrapie infectivity. Neurology.
1991;41(9):1482-1490.
[141] Buxbaum JN, Linke RP. A molecular history of the amyloidoses. J Mol Biol.
2012;421(2):142-159.
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[142] Sabate R, Rodriguez-Santiago L, Sodupe M, et al. Thioflavin-T excimer formation upon
interaction with amyloid fibers. Chem Commun. 2013;49(51):5745-5747.
Appendices:
Alzheimer’s disease (AD); Amyloid beta 1-42 (Aβ 1-42/ Aβ42); Amyloid precursor protein
(APP); Amyotrophic lateral sclerosis (ALS); Bovine Spongiform Encephalopathies (BSE);
Central nervous system (CNS); Creutzfeldt Jacob Disease (CJD); Follecular Dendritic Cells
(FDC); Functional bacterial amyloid (FuBA); Gastrointestinal (GI); Interlukin (IL); Lipo poly
saccharide (LPS); Mixed lineage kinase domain like protein (MLKL); Multiple System atrophy
(MSA); Parkinson’s Disease (PD); Pathogen associated molecular pattern (PAMP); Prion
Forming Domain (PFD); Prion Protein- Cellular (PrPC); Prion Protein- Scrapie (PrPSc); Receptor
interacting kinase 1 (RIP1); Receptor interacting kinase 3 (RIP3); RIP homotypic interaction
motif (RHIM); Shy-Drager syndrome (SDS); Thioflavin T (ThT); Toll like receptor (TLR);
Triggering receptor expressed in myeloid/microglial cells-2 (TREM2).
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Figure 1: A: Biogenesis of Curli fibers. Curli protein components- CsgG, F, E & D are
synthesized from one operon and CsgB, A & C from another. SecYEG (Sec tagged Curli
protein) secretes in periplasm and help making passage for Csg components. CsgC, E & G
altogether form a pore through which CsgF, B and soluble CsgA pass and come outside where
CsgB function as a nucleus to fibrillize CsgA monomers. CsgD acts as a regulator for
transcription of csgBAC operon. B: Biogenesis of fibrillar coating outside the arial hyphae of
Streptomyces coelicolor by Chaplin proteins. ChpA – ChpH diffuse out of the cell and form
insoluble layer of 4-6 nm wide fibrils between air and soil interface. This rigid film helps the
arial hyphae penetrating the soil barrier by lowering the water surface-tension. The change in
hydrophobicity in the reproductive aerial hyphae prevents it from growing back into the aqueous
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substrate and thus facilitates the dispersion of spores in wind.
Figure 2: Schematic representation showing clearance of Aβ42 monomer through
recognition by TREM2, Aβ fibril via TLR2 and functional bacterial amyloid (FuBA) via
TLR2. In brain, Aβ monomers are produced from Amyloid-β precursor protein (APP) through a
sequential cleavage by β and γ secretase enzymes. Mutations in presenilins (a component of γ
secretase) increase the production of Aβ42 which lead to the Amyloid β oligomerization, fibril
formation and ultimately senile plaque formation. Triggering receptor expressed in
myeloid/microglial cells-2 (TREM2) in association with the membrane-spanning linker protein
TYROBP clear these amyloid β monomers through phagocytosis and Toll Like Receptors-2
(TLR2) clear the fibrils. The ROS generated via TLR2 signaling pathway down-regulate TREM2
and thus Aβ42 monomer clearance via TREM2 is inhibited. There is still some lack of evidence
that FuBA (functional beta amyloids) cross the Blood Brain Barrier (BBB) but there is evidence
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that, FuBA also down-regulate TREM2 expression via ROS generation. Thus in this scenario,
the lack of clearance of amyloid beta monomers increases the rate of senile plaque formation.
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Figure 3: Schematic representation showing infectious prion protein- PrPSc replication
hypothesis. According to this hypothesis, a pathogenic PrPSc molecule exists in a fibrillar form,
which when transmitted into a healthy individual, binds normal, cellular prion- PrPC molecules.
With the subsequent conformational change of PrPC molecule to that of PrPSc, the PrPSc-fibril
elongates. In the following steps, more and more cellular prions (PrPC) are converted to PrPSc
form through the conformational change induced by infection seed i.e. the first infectious PrPSc
fibril and are added up to the growing PrPSc chain, resulting in the linear increase of PrPSc-fibril.
The exponential growth of pathogenic PrPSc molecules takes place with the aid of a reverse
breakage step, generating multiple new PrPSc seeds from elongated PrPSc-fibril. This facilitates
amyloid plaque formation through the aggregation of the newly synthesized PrP Sc-fibrils.
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Table 1: β-Amyloids are diverse among organisms with varying functions
Organis
Amyl Primary Amino Acid Sequencea (Related)
ms
oid
mental
Prote
Evidenc
in
e
Bacteria
Curli
- E. coli,
(Csg
GTNNATGVLQFGGTN------
Function
Experi
Ref
Biofilm
EM,
[121,
formation,
Congo
37].
Salmonel A)
host
red,
la spp.
invasion.
ThioT
SASVGQAGMNNFAFVGQTG.
and CD.
Streptom
Chapl GMASATDG-
yces sp.
ins
GAHAHGKAVGSPGVASGNLVQAPIHIPVNAVGNSVN
Modulation
CD,
of water
ThioT
surface
and EM.
[44]
VIGVLNPAFGNLGVNH.
tension (i.e.
developme
nt of aerial
structures).
Pseudom FapC
onas
Not reported
Fimbriae
Congo
formation.
red,
fluoresce
TEM,
ns
FTIR,
Tandem
MS.
[122]
Klebsiell
Micr
TVRAQSEFYVTQTFG-SI---G-EYMAPGTPLV—
Cytotoxin-
Congo
a
ocin-
EGYDTANFS-LSITLPPFYAEL-----FPHMDFFR---------
forms pores
red,
R
in
EM,
pneumon E492
ia
[123]
cytoplasmic CD,
membrane
MALDI
of
-TOF.
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Enterobact
eriaceae.
MYRFACRTLMLAACILATGVAGLGVGAQSAAQTAP
Adhesive
Congo
terium
VPDY YWCPGQPFDPAWGPNWDPYTCHDDFH
properties
red,
tubercul
RDSDGPDHSRDYPGPILEGPVLDDPGAAPPPPAAG
on pili.
TEM.
osis
GGA
Regulation
EM,
of
CD,
ra
heterokaryo
FTIR,
anserine
n
Congo
formation.
red and
Mycobac
MTP
Fungi
HET-
Podospo
s
Not reported
[124]
[30]
NMR.
Sacchar
URE
(Upto 50th AA-out of total 350
Regulation
Electron
omyces
2p
residues.)MMNNNGNQVSNLSNALRQVNIGNRNS
of nitrogen
diffracti
NTTTDQSNINFEFSTGVNNNNNNN
catabolism.
on, X-
cerevisia
e
ray,
Congo
[125]
red, EM
and
ThioT.
Sacchar
Sup3
(Upto 50th AA-of 680 residues.)
Regulation
EM,
omyces
5p
MSDSNQGNNQQNYQQYSQNGNQQQGNNRYQG
of stop-
Congo
YQAYNAQAQPAGGYYQNYQ
codon read-
red, CD
through.
and X-
cerevisia
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e
[126]
ray.
Most
Hydr
(Upto 50th AA out of 110 residues)
Fungal coat
AFM,
[127,
fungi
oph-
MISRVLVAALVALPALVTATPAPGKPKASSQCDVGEI
formation,
CD,
128]
obins
HCCDTQQTPDHTS
modulation
FTIR,
of adhesion
ThioT,
and surface
NMR,
tension.
Congo
red and
X-ray.
Animali
Chori
(Upto 50th out of 110 AA residues of D.
Structural
Congo
a-Insects
on
melanogaster)
and
red, X-
and fish
protei MKYLIVCVTLALFAYINASPAYGNRGGYGGGYGGGY
protective
ray,
functions in
EM,
the
FTIR
eggshell.
and CD.
Structural
EM and
ns
Nephila
Spidr
GPVQRVVYEEVPAY
Not reported
[129]
[130]
clavipes
oins
(i.e. spider
CD.
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silk).
Homo
Pmel
Upto 50th out of 660 residues-
Scaffolding
X-ray,
sapiens
17
MDLVLKRCLLHLAVIGALLAVGATKVPRNQDWLGV
and
Congo
SRQLRTKAWNRQLYP
sequestratio
red, EM
n of toxic
and
intermediat
ThioT.
[5]
es during
melanin
synthesis.
EM, Electron Microscopy; CD, Circular Dichroism Spectroscopy; ThioT, Thioflavin-T test; TEM,
Transmission Electron Microscopy; FTIR, Fourier Transform Infra Red spectroscopy; MS, Mass
Spectroscopy; MALDI-TOF, Matrix Assisted Laser Desorption Ionization-Time of Flight; NMR,
Nuclear Magnetic Resonance; AFM, Atomic Force Microscopy;
a
mentioned in one letter amino acid code.
Table 2: The overall comparison between Aβ42- Prions- Functional amyloids
Comparison
Names of different amyloids
parameters
Disease assotiated amyloids
Functional amyloids
Occurrence
Covering a huge range
Aβ42 of Alzheimer’s
Prions
Human being
Mammals, mainly
sheep, cows and
sapiens.
Structure
humans.
 Filamentous,
branched
uncross-β-
Intermolecular-
 Mammalian
hydrogen-bonded
cellular prion
sheet structures with
beta-sheet that
PrPC is a α-
indefinite length and
yields twisted fibers
helical
a diameter of about
of about 10 nm
transmembrane
2-20 nm.
diameters & the
protein but
senile plaques of
misfolded PrPSc
AD are made up of
is a β-amyloid
long, unbranched 4-
fiber.
10 nanometer wide
fibers.
DISSIMILARITIES
DISSIMILARITIES
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from E. coli to Homo
 Most
frequently  Stacking subunits
employs the stacking
may not be stably
of folded subunits.
folded
by
−
 Possess
themselves.
 Possess parallel in-  Structural
register
β-sheet
architectures
or anti-parallel βare
(Ure2, Sup35, Rnq1,
of parallel & anti-
Pmel17),
parallel β-sheets.
β-helices
parallel
sheet structure.
(HET-s, CsgA) and
swapping
(Hydrophobins)
Function
Varying
range-
from Aβ42
fibrils
by PrPSc
generates
biofilm formation/ host accumulating as senile amyloid plaques and
invasion/ development of plaques
DISSIMILARITIES
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domain
cause causes
spongiform
aerial
structures/ neurodegeneration in encephalopathy,
Fimbriae
formation/ AD.
particularly BSE in
Adhesive properties on
cows,
pili/ working as toxins/
sheep & CJD in
Regulation
humans.
of
heterokaryon
formation/Regulation of
nitrogen catabolism & so
on.
scrapie
in
Misfolded proteins
Misfolded
and/or Mode monomers secret outside
after synthesis start
nucleates
of action
& assemble together;
chain elongation; e.g.,
oligomerization
e.g., CsgA secretes
Aβ42 monomers
cellular prions; e.g.,
outside the cells→ CsgB
aggregation→ Aβ42
entry of infectious
nucleates fibrillization of
oligomers→
PrPSc fibril in host→
CsgA→CsgG acts as
Aggregation of
addition
outer membrane pore→
oligomers→Senile
monomers
For structural FuBA-
secretes CsgA and CsgB. plaque formation.
DISSIMILARITIES
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Biogenesis
fibril→
prion
of
PrPC
of
to
this
pathogenic
fibril
extention→
fibril
breakage→
exponential increase
PrPSc→
in
accumulation
of
plaques→encephalo
pathy.
Role in
FuBA functions as a
Aβ is considered to be Contagious
disease
toxin & may cause
the causative agent of fibril
formation
disease in host e.g. MTP
disease (AD) onset.
of M. tuberculosis.
nucleus
acts
in
PrPSc
as
a
prion
plaque deposition.
CsgA contains the
Aβ42 acting as a
After entry via M-
response
(PAMP) that is
PAMP [133], is
cells, encountered by
recognized by TLR2
recognized by TLR2
epithelial
[131] & induce IL-17A,
on microglia [134],
replicates in FDC→
drives NF-kB signaling
which leads to
in
CNS
activates
and cyclooxygenase-2
neuropathology via
TLR4/9→
induces
activation [132].
inflammation [135].
IL4, IL10, IL13→
TLRs→
sustains
in
macrophages
[136,137].
Solubility
Having a common beta strand rich structure all the above amyloids
appear as an insoluble biomolecule and treatment with formic acid or
hexa-fluoro-2-propanol is required to liberate monomers from these fibers
[36].
Resistance
SIMILARITIES
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DISSIMILARITIES
Immune
FuBAs or disease assotiated amyloids like Aβ42 or prion proteins (PrPSc)
are highly resistance to protease digestion [138-140].
Staining-
Congo red which stains the beta-pleated sheet structures can stain both
detection &
these pathogenic Aβ42 and bacterial amyloids [141]. Congo red staining
spectral
results in a red shift in spectro-photometer analysis and green
pattern
birefringence under polarized light [36]. Amyloids belonging to any
category, gives a positive thioflavin T test (ThT) resulting in increased
fluorescence [142].
Evolutionary
Different types of amyloids are beyond evolutionary selection constrain.
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relationship
Table 3: Symbolic notations used for the mathematical equation and corresponding units
Symbol
Notation
X
ThT fluorescence intensity at 460 nm to 520 nm. Units: absorbance units
(AU) or (%).
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t
Time. Units: h or d.
Xm
Maximum aggregation growth. Units: AU or %
vm
Maximum aggregation rate. Units: AU/h, AU d−1 or % h-1

Lag phase. Units: h or d.
Xm•
Maximum aggregation affected by functional amyloid. Units: AU or %
vm•
Maximum aggregation rate affected by functional amyloid. Units: AU/h,
AU d-1 or % h-1
•
Lag phase affected by functional amyloid. Units: h or d
C
Concentration of functional amyloid. Units: mM or μM.
Kx
Maximum response affecting on Xm Dimensionless
mx
Concentration corresponding to the semi-maximum response affecting
on Xm Units: mM or μM
ax
Shape parameter affecting on Xm Dimensionless
Kv
Maximum response affecting on vm Dimensionless
mv
Concentration corresponding to the semi-maximum response affecting
on vm Units: mM or μM
av
Shape parameter affecting on vm Dimensionless
K
Maximum response affecting on  Dimensionless
m
Concentration corresponding to the semi-maximum response affecting on
 Units: mM or μM
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a
Shape parameter affecting on  Dimensionless
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