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10.2 O-GlcNAc Transferase (OGT) and O-GlcNAc Hydrolase (OGA) in Neurodegeneration
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than that of Thiamet-G. Interestingly, some of the new structures were able to
increase protein O-GlcNAc levels (Table10.6).
As compound bioavailability was moderate to very good, compound differentiation was made through pharmacodynamic effects. For the most promising compounds exhibiting potent hOGA inhibition (K
6
measurable permeability (>2
cm s1), as well as for the 5-difluoromethyl deriv-
× 10
<20 nM), EC50 <200 nM, and
i
atives 83–86, the pharmacodynamic effect of OGA inhibition in the CNS was evaluated by measuring the time-dependent accumulation of total O-GlcNAc protein in
rat brain after a single oral dose of inhibitor and data was collected after 8 and
24
hours of dose intake[67]. Inhibitor concentration in plasma and in brain homogenate was also evaluated to compare distributional delay in brain exposure (Table10.2).
Compounds 80 and 81 have both a greater effect at eight hours than compound 65
(Thiamet-G) but 81 shows an interesting high level of O-GlcNAc protein for a low
brain exposure when compared to compounds 80 and 65. Compounds 84 and 85
have also demonstrated significant effects and a good brain exposure[67].
In conclusion, the potent and selective hOGA inhibitors, exhibiting biodistribution to the CNS, also afford increased O-GlcNAc protein levels. Among all tested
compounds, 86 (MK8719) stood out with a balanced brain and plasma exposure and
a greater efficacy over Thiamet-G, possibly resulting from its greater brain exposure,
as the brain AUC value (area under the plot of inhibitor concentration in the brain
–1
vs. time after dose intake) for a dose of 10
–1
24
hours was 9.64 nM h g
, while that of Thiamet-G was only 1.14 nM h g–1[67].
mg kg
of 86, at time points 1, 4, 8, 12, and
The production of MK8719 (86) was carried out starting from compound 65
(Thiamet-G) (Scheme10.11). Boc protection of the amino group was followed by
321
Scheme 10.11 Synthesis of MK8719[67]. Reagents/solvent and yield: (a) Boc2O, iPr2NEt,
DMF/MeOH, 64%; (b)TBDMSCl, imidazole, 76%; (c) BzCl, DMAP, 71%; (d) AcCl, MeOH, 90%; (e)
Dess-Martin periodinane reagent (DMP), pyridine, DCM, 0 °C–rt; (f) DAST, DCM, 40%; (g)
K
, MeOH, 92%; (h) TFA, DCM, 95%.
2CO3
10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
322
regioselective protection of the primary alcohol by reaction with tercbutyldimethylsilyl chloride (TBDMSCl). Benzoylation of the free hydroxy groups of
88 followed by cleavage of the silyl group afforded compound 89, whose primary
alcohol was oxidized to aldehyde with Dess–Martin periodinane, further reacting
with DAST to give compound 90 in 40% yield over the two steps. Deprotection with
potassium carbonate to generate the hydroxy groups and with TFA for Boc cleavage
afforded MK8719 (86) in 10.9% overall yield from Thiamet-G[67].
The hypothesis whereby increasing O-GlcNAc levels in Tau hinders Tau aggregation was recently investigated by Wang etal.[69] by applying MK8719 invivo in a
rTg4510mouse model of tauopathy. As O-GlcNAcylation levels are reduced in AD
brains, and the decrease of Tau O-GlcNAc levels is correlated with increased tau
hyperphosphorylation, resulting in the formation of insoluble Tau aggregates, inhibition of OGA by MK8719was envisioned as a strategy to attenuate Tau aggregation.
It was found that oral administration of MK8719 to a rTg4510 mouse model of
human tauopathy results in a significant increase of brain O-GlcNAc levels and
reduction of pathological Tau, accompanied by attenuation of brain atrophy with
reduction of forebrain volume loss as observed by volumetric magnetic resonance
imaging. Although these are encouraging results for the usefulness of OGA inhibitors in reducing Tau pathology, it is crucial to understand the physiological and toxicological consequences of O-GlcNAc elevation in vivo, as there are many
O-GlcNAcylated proteins that may also be influenced by OGA inhibition[69].
10.3 GalNAc in Neurodegeneration
In 2017, the relationship between AD and O-GalNAcylation was reported in several
studies. Akasaka-Manya etal.[34] used real-time PCR to analyze the expression of
human brain GalNAc-transferases (GalNAc-Ts), which transfer GalNAc from UDPGalNAc to Ser or Thr residues, and showed that the expression of several GalNAc-Ts
was altered with sporadic AD progression. To evaluate the impact of GalNAc-Ts
overexpression on Aβ production, GalNAc-T1, GalNAc-T4, and GalNAc-T6 were
transfected into HEK293T cells. Briefly, while GalNAc-T1 and GalNAc-T4 reduced
Aβ1–40 formation, GalNAc-T6 reduced the production of both Aβ1–40 and Aβ1–42.
From all three GalNAc-Ts, GalNAc transferase activity on APP was more relevant
for GalNAc-T6, suggesting that enhanced O-glycosylation on APP by
GalNAc-T6inhibits Aβ production. GalNAc-T1, GalNAc-T4, and GalNAc-T6were
transfected into HEK293T cells to overexpress them and determine their effect on
Aβ production. Transfection of GalNAc-T6 significantly reduced the generation of
both Aβ1–40 and Aβ1–42
formation. Although the three GalNAc-Ts showed enzymatic activity on soluble
APP, the activity of GalNAc-T6 on APP was the most prominent one. The expression
of α-secretase and BACE1was slightly altered in the transfected cells, but the activity of both secretases was not significantly altered. Their data suggested that excess
O-glycosylation on APP by GalNAc-T6 inhibits Aβ production [34]. In 2020
Akasaka-Manya and Manya[70] reported that the reduced Aβ generation by coexpression of APP and GalNAc-T6 resulted from a decrease of β-cleavage, while the
expression level of membrane-bound APP did not change. As possible explanations
while GalNAc-T1 and GalNAc-T4 only reduced Aβ1–40
,
10.3 GalNAc in Neurodegeneration
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for the β-cleavage decrease, they suggest that either glycosylated APP is not transported to the location for β-cleavage, or BACE1 cannot approach glycosylated APP
resulting from conformational changes. However, the upregulation of GalNAc-T6
observed in AD brains and the protective effect of GalNAc-T6 acting against Aβ
generation remain contradictory, urging for further research to understand these
results[70].
An interesting study highlighting the role of O-GalNAcylation on the amyloidogenic
property of glycopeptides was carried out by Lin etal. in 2014[14]. The authors showed
that GalNAc α-O-linked to Ser135 residue of the prion peptide PrP(108–144), whose
structure suffers a coil-to-β conversion associating into amyloid fibrils, had a prominent effect on the conformation of the polypeptide chain and inhibited amyloidogenesis. They suggested that the acetamido group in the equatorial position of GalNAc
carbon 2 is important in the interaction between sugar and peptide, because the antiamyloidogenic effect was not found when the sugar α-linked to Ser135was galactose.
Another study by Liu etal. in 2017[71] has shown that by reducing GalNAc-T2
activity with its competitive inhibitor luteolin, a tetrahydroxyflavone, the generation of total Aβ, Aβ1–40
and Aβ1–42was reduced in a dose-dependent manner in
,
cells coexpressing APP and GalNAc-T2. GalNAc-T1, GalNAc-T3, and GalNAc-T13
transfer GalNAc to APP as well but only GalNAc-T3was also inhibited by luteolin.
They found that both sAPPα and sAPPβ were reduced, suggesting that the process
occurs prior to the intervention of secretases, and demonstrated that reduction of
Aβ production resulted from the decrease of APP O-GalNAcylation. In addition,
they have shown that the inhibitor luteolin also reduced Aβ production in the brain
of APP/PS1 transgenic mice.
GalNAc is a residue present in complex molecules, the GAGs and the PGs, which
together with proteins compose the cerebral extracellular matrix. Their accumulation surrounding certain neurons forms the perineuronal nets (PNNs) [72–75],
whose components are synthesized by neurons, astrocytes, and oligodendrocytes,
and form a unique environment. The major PNNs component is hyaluronan, a polysaccharide composed of disaccharide repeating units of glucuronic acid and GlcNAc.
It is the only PNN GAG that is not bound to sulfate nor to a core protein. Other components are chondroitin sulfate proteoglycans (CSPGs), where GAGs are linked to a
core protein and contain repeating units of disaccharides composed of an amino
sugar (GalNAc or GlcNAc) and galactose or a uronic acid, namely glucuronic or iduronic acid. PNNs also contain hyaluronan and PGs binding proteins[73]. PNNs function as a neuron physical barrier, also forming a polyanionic microenvironment
around neurons. They participate in brain signaling pathways and in synaptic plasticity and change from physiological to pathological conditions[73]. Baig etal.[72]
showed, in 2005, that there is substantial loss of GalNAc from PNN CSPGs from the
frontal cortex in AD, indicating a degradation of PNN composition around neurons
and certainly affecting PNN functions that depend on GalNAc containing CSPGs
side chains[72]. The authors concluded that further studies are required to characterize PNN degradation processes and their effects on AD. Indeed, further investigation on PNN has demonstrated its importance in controlling plasticity, regulating
axonal growth and regeneration, and in memory storage. Inspired by modulating
PNNs, either by targeting interactions with PNN core components or through PNN
digestion, new options emerge for drug development in AD therapy[75].
323
10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
324
10.4 Chitosan and Derivatives in AD Brain
Chitin is a linear polymer of β-(1→4) linked GlcNAc residues found in crustacean’s
exoskeletons and fungi’s cell walls. It is the second most abundant natural polymer
on earth and has been widely used in the field of biomaterials due to its nontoxic
nature, biocompatibility, and biodegradability[76]. From chitin deacetylation, CTS,
a linear polymer of β-(1→4) linked β--glucosamine (GlcN), can be obtained.
Chitosan oligosaccharides (COSs) are biodegradation products of CTS or chitin,
with low molecular weight and high-water solubility, due to their shorter chain
lengths and free amino groups, making them easily absorbed by the human intestine[77]. CTS, COS, and their derivatives also possess antioxidant, anti-HIV, antiinflammatory and neuroprotective effects[77].
Neuroinflammation results in oxidative stress in the synapses and mitochondria,
contributing to neuronal and vascular degeneration in AD brain. Water-soluble CTS
was found to have beneficial effects against the inflammatory response associated
with Aβ, which induces inflammation by the production of pro-inflammatory
cytokines tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) in the brain. The
secretion of both cytokines in human astrocytoma cells was induced by Aβ25–35
and interleukin-1β (IL-1β), a critical neurotoxic component in AD, the levels of
which are increased in AD patients[78]. Kim etal. showed that pretreatment with
water-soluble CTS (1 μg ml
both TNF-α and IL-6. In addition, considering that Aβ25–35induces the production
of nitric oxide by regulating nitric-oxide synthase in neuroglial cells, and higher
levels of this enzyme surround Aβ and produce neurotoxicity in astrocytes, damaging AD brain, the authors[78] also showed that expression of nitric oxide synthase
is partially inhibited by treatment with water-soluble CTS. These experiments confirmed that the water-soluble CTS used has, indeed, regulatory effects on human
astrocytes.
Jiang etal.[79] evaluated the activities of N-acetyl COS (NA-COS) in neurodegeneration. The results of their work demonstrated that NA-COS significantly improved
learning and memory of AD rats. Furthermore, hematoxylin and eosin (HE) staining of brain tissue sections showed that NA-COS was able to diminish hippocampal
neurodegeneration induced by Aβ25–35, while the treatment of intrahippocampal
with NA-COS decreased hippocampal AChE and malondialdehyde levels, with an
increase in ACh concentrations. In addition, with NA-COS treatment, antioxidant
enzyme levels (superoxide dismutase and glutathione peroxidase) in rat’s hippocampus were also enhanced[79].
Recently, alendronate (ALN)-loaded CTS nanoparticles (CTS-ALN-NPs) for brain
delivery by a noninvasive intranasal route were investigated. CTS-ALN-NPs reduced
the peripheral side effects and released ALN directly into brain. The in vitro and
ex vivo release profiles revealed a sustained drug release through CTS-ALN-NPs
when compared to the pure drug solution. Furthermore, intranasal CTS-ALN-NPs
were evaluated against intracerebroventricular-streptozotocin (ICV-STZ), which
induces AD-like pathologies in mice[80]. The intranasal CTS-ALN-NP altered the
ICV-STZ-induced neurobehavioral, neurochemical, and histopathological changes
1
and 10 μg ml1) significantly inhibited secretion of
10.5 Cholinesterase Inhibitors
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in mice. The treatment of these mice with CTS-ALN-NPs resulted in a reduction of
the neuroinflammatory cytokines IL-6, IL-1β, and TNF-α levels in the hippocampus, which highlights the anti-inflammatory activity of ALN. The effect of ALN was
found to be more pronounced when administered in the form of CTS-NPs intranasally, which allowed the direct release of ALN into the brain, hence avoiding passage through the gastrointestinal tract[80].
The cholinergic neurotransmission mediated by ACh has a well-known role in
modulation of learning and memory[81]. Indeed, the attenuation of ACh levels due
to the aggravating activity of AChE and BChE enzymes significantly contributes to
cognitive disabilities[82]. AChE and BChE levels were increased in the hippocampus of mice that received ICV-STZ injections, accompanied by important reductions
in memory and learning abilities. In contrast, a drop in the levels of both ChEs was
noticed after treatment with CTS-ALN-NPs, revealing that ALN is capable of reversing deficits in cognitive and cholinergic functions[80]. Furthermore, the inhibition
of STZ-induced BACE-1 overexpression was observed in the hippocampus of mice
treated with a subdiabetogenic ICV-STZ followed by the intranasal administration
1
of CTS-ALN-NPs for 15
days (0.0352 mg kg
), along with reductions in Aβ1–42levels. Interestingly, CTS-ALN-NPs led to stronger reductions in BACE-1 and Aβ1–42
peptide levels when compared to an ALN pure solution. These results show that
CTS-ALN-NPs are capable of attenuating pathological changes observed in AD[80].
325
10.5 Cholinesterase Inhibitors
As previously referred, AD is a multifactorial neurodegenerative brain disorder, and
its exact pathophysiology is not yet entirely known. One of the variables that has a
direct link to AD is the cholinergic system, which directly contributes to regulation
and memory processes and, therefore, represents a target for AD drug design [83].
Early studies involving AD’s patients found an altered cholinergic activity, which
resulted in cognitive and functional symptoms[84]. The two major forms of ChEs, in
mammalian tissues, are AChE EC 3.1.1.7 and BChE EC 3.1.1.8. Both belong to the
group of Ser hydrolases and are responsible for the breakdown of the neurotransmitters ACh and butyrylcholine (BCh), respectively[85]. AChE is substrate specific in
nature and is found in high concentrations in the brain, while BChE is nonspecific
and is distributed throughout the body. Under normal conditions, ACh is dominantly
decomposed by AChE. Both enzymes exhibit different kinetic characteristics, depending on ACh concentrations. When ACh concentration is low, AChE’s activity is major,
whereas BChE presents higher activity when ACh concentration is elevated. In progressed AD, AChE in brain declines to 55–67% of normal values while BChE increases
to 120% of normal levels, indicating that BChE plays a critical role in ACh hydrolysis,
at a late stage of AD[83]. In fact, it has been reported that the specific inhibition of
BChE is important for raising ACh levels and improving cognition [86]. Hence,
designing selective, potent, and well-tolerated inhibitors of each ChE became a challenge for the scientific community, in order to determine which enzyme needs to be
targeted for maximum effect in treating AD. Currently, there are some approved ChE
10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
326
Scheme 10.12 Synthesis of the N9 and N7 nucleosides 92 and 93, respectively. Reagents/
solvent and yield: (a) BSA, 2-acetamido-6-chloropurine, TMSOTf, (CH
Cl)2, 85 °C, 25% for 92
2
and 37% for 93. Source: Adapted from Marcelo etal.[88].
inhibitors, namely donepezil, rivastigmine, and galantamine, which help in controlling the symptoms of AD and do not treat the underlying disease or delay its progression[87]. In this perspective, Rauter and coworkers explored purine nucleosides as
ChE inhibitors. Marcelo etal.[88], developed the first synthesis of 2-acetamidopurine
nucleosides 92 and 93 starting from compound 91 incorporating a tetrahydrofuran
ring fused to the pyranose (Scheme10.12). The bicyclic sugar 94 was also modified to
generate the elongated carboxylic ester appendage bearing the azido group at position
6 (97a,b, Scheme 10.13). For the purpose, Swern oxidation followed by a Grignard
reaction afforded the allyl alcohols 95a,b. Ozonolysis followed by sodium chlorite oxi-
dation in tBuOH/H
O/2-methylbut-2-ene (2:2:1) afforded the corresponding car-
2
boxylic acids, which were esterified to give the benzyl esters 96a,b. Triflation and
Scheme 10.13 Synthesis of the (6′S)- and (6′R)-configurated N7 nucleosides 98a and 98b.
Reagents/solvent and yield: (a) 1. (COCl)
steps; (b) 1. O
(2:2:1); 3. BnBr, KHCO
NaN
, DMF, 72% for 97a, 86% for 97b both over two steps; (d) BSA, 2-acetamido-6-
3
chloropurine, TMSOTf, CH
, DMS, DCM; 2. NaClO2, NaH2PO4.H2O, tBuOH/H2O/2-methylbut-2-ene
3
, Bu4NI, DMF, 68% over three steps; (c) 1. Tf2O, pyridine, DCM; 2.
3
CN, 60% for 98a and 55% for 98b. Source: Adapted from Marcelo
3
, DMSO, Et3N; 2. CH2=CHMgBr, THF, 65% over two
2
etal.[88].
10.5 Cholinesterase Inhibitors
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nucleophilic substitution with sodium azide afforded the diastereoisomers 97a and
97b in high yield. With these two bicyclic intermediates, coupling with silylated
9
2-acetamido-6-chloropurine catalyzed by TMSOTf afforded a mixture of N
- and N7-
linked (98a and 98b) nucleosides, which were screened for AChE and BChE inhibi-
7
tion. While none of the compounds tested inhibited AChE, the N
nucleosides showed
potent inhibition toward BChE (Table10.7). Nanomolar inhibition was obtained for
Table10.7 Inhibition (%) of BChE for different concentrations of the compounds tested
and IC
values.
50
327
Compound nr Concentration (μg ml−1) BChE inhibition (%) BChE IC50± SEM
92 100.00 48*** -----
10.00 11
93 100.00 84*** 0.76 ± 0.05
10.00 85***
1.00 70***
0.10 20***
97a 100.00 91*** 4.20
± 0.05
10.00 64***
1.00 36***
0.10 15*
97b 100.00 98*** 13.40
± 0.80
10.00 73***
1.00 14**
98a 100.00 81*** 22.00 ± 1.60
10.00 34***
1.00 9
98b 100 91*** 0.14
± 0.01
10 79***
1 77***
0.1 63***
0.01 10
Rivastigmine
b
100 100*** 0.17 ± 0.01
10 100***
1 100***
0.1 76***
0.01 NI
a
a) IC50 compound concentration inhibiting 50% of enzyme activity; values are expressed as
mean ± standard error of the mean (SEM).
b) Rivastigmine is a drug to treat AD patients and was used as positive control.
***P< 0.001, **P< 0.01, *P< 0.05, NI: no inhibition. Source: Adapted from Marcelo etal.[88].
10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
328
Scheme 10.14 Synthesis of the N9 and N7 nucleosides 99 to 122 as reported by Schwarz
etal.[89] Reagents/solvent and yield: (a) BSA, 6-chloropurine (CP) or 2-acetamido-6chloropurine (ACP), TMSOTf, CH
R
=βN7CP, 20%; 100: d-Glc, R1=Ac, R2=βN9CP, 41%; 101: d-Glc, R1=Bn, R2=αN7CP, 6%; 102:
2
d-Glc, R
=Bn, R2=βN7CP, 17%; 103: d-Glc, R1=Bn, R2=αN9CP, 10%; 104: d-Glc, R1=Bn, R2=βN9C P,
1
45%; 105:
R
=β-N9CP, 43%; 108: d-Man, R1=Bn, R2=αN7CP, 17%; 109: d-Man, R1=Bn, R2=βN7CP, 14%;
2
110:
R
=αN7ACP, 7%; 113: d-Glc, R1=Bn, R2=βN7ACP, 34%; 114: d-Glc, R1=Bn, R2=βN9ACP, 29%; 115:
2
d-Gal, R
R
=αN9ACP, 10%; 118: d-Gal, R1=Bn, R2=βN9ACP, 41%; 119: d-Man, R1=Bn, R2=αN7ACP, 8%;
2
120:
R
=Bn, R2=βN9ACP, 3%. Source: Adapted from Schwarz etal.[89].
1
d-Gal, R
d-Man, R
=Bn, R2=αN7ACP, 3%; 116: d-Gal, R1=Bn, R2=βN7ACP, 44%; 117: d-Gal, R1=Bn,
1
d-Man, R
=Bn, R2=β-N7CP, 12%; 106: d-Gal, R1=Bn, R2=αN9CP, 7%; 107: d-Gal, R1=Bn,
1
=Bn, R2=αN9CP, 27%; 111: d-Man, R1=Bn, R2=βN9CP, 10%; 112: d-Glc, R1=Bn,
1
=Bn, R2=βN7ACP, 28%; 121: d-Man, R1=Bn, R2=αN9ACP, 24%; 122: d-Man,
1
CN, microwave irradiation (150 W); 99: d-Glc, R1=A c ,
3
compound 98b competing well with rivastigmine, a drug currently in use for the treatment of AD[88]. Experimental results showed that the presence of benzyl groups on
7
the carbohydrate scaffold and the N
-linked purine nucleobase were required for the
strong BChE inhibition[84]. The preliminary evaluation of the acute cytotoxicity of
the elongated bicyclic sugar precursors and nucleosides was also performed indicating low values, in the same order of magnitude as those of rivastigmine[88].
In 2014, Rauter and coworkers[89] presented a novel microwave-assisted synthesis
and anticholinesterase activity of a series of 24new purine nucleosides incorporating
6-chloropurine or 2-acetamido-6-chloropurine linked to -glucosyl, -galactosyl and
-mannosyl residues, with very interesting results compared to those previously
obtained by Marcelo etal.[88]. Optimization of the reaction conditions adapted to
formation of the new nucleoside structures was achieved by the use of microwave
irradiation (150 W, 65 °C), reducing the reaction time from 2 hours to 15 minutes
(Scheme10.14)[89]. Compound structure was designed aiming at ChE (AChE and
BChE) inhibition efficiency and selectivity by investigating sugar stereochemistry,
7
purine structure, and N
or N9-linked purine ligation to the sugar (Table10.8). The
outcome of this work showed that α-anomers were the most active compounds.
Regarding BChE inhibition, the nucleosides 110, 112, 119, and 120 were noticeably
more potent than the drug galantamine, and the most promising competitive and
7
selective BChE inhibitor, the N
showed a K
of 50 nM and a selectivity factor of 340-fold for BChE over AChE[89]. To
i
the best of our knowledge, compound 119 shows the lowest K
-linked 2-acetamido-α--mannosylpurine 119,
for BChE, being one of
i
the best candidates toward the study of BChE selective inhibition against AD, when
compared to other newly reported carbohydrate-based[90, 91] and noncarbohydratebased compounds[82]. Interestingly, selectivity over AChE or BChE can be tuned by
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Table10.8 Inhibitory constant Ki for nucleosides 99–123 as determined by Elman's assay
with BChE and AChE in comparison to galantamine hydrobromide.
329
Compound
BChE Ki
(μM)
AChE Ki
(μM) Compound BChE Ki (μM)
AChE Ki
(μM)
99 β-Glc-N7CP >100 28.9 ± 2.1 111 β-Man-N9CP >20 >20
100 β-Glc-N
101 α-Glc-N
102 β-Glc-N
103 α-Glc-N
104 β-Glc-N
105 β-Gal-N
106 α-Gal-N
107 β-Glc-N
108 α-Man-N
109 β-Man-N
110 α-Man-N
Galantamine
hydrobromide
Source: Adapted from Schwarz etal.[89].
9
CP >100 17.5 ± 2.6 112 α-Glc-N7ACP 2.5 ± 0.3 >10
7
CP >20 9.6 ± 2.3 113 β-Glc-N7ACP >100 23.0 ± 1.9
7
CP >2 >2 114 β-Glc-N9ACP >2 >2
9
CP >100 17.0 ± 2.0 115 α-Gal-N7ACP 50.0 ± 7.0 42.0 ± 9.2
9
CP >100 16.0 ± 2.7 116 β-Gal-N7ACP >20 >20
7
CP >20 >20 117 α-Gal-N9ACP >2 >2
9
CP >10 5.6 ± 0.8 118 β-Gal-N9ACP >2 >2
9
CP >100 25.6 ± 2.1 119 α-Man-N7ACP 0.05 ± 0.01 18.1 ± 4.8
7
CP 30.9 ± 2.2 23.4 ± 3.6 120 β-Man-N7ACP 1.4 ± 0.1 3.0 ± 0.3
7
CP 9.6 ± 0.7 28.5 ± 6.5 121 α-Man-N9ACP 10.3 ± 2.6 17.1 ± 2.5
9
CP 2.8 ± 0.3 2.4 ± 0.3 122 β-Man-N9ACP >10 >10
9.4 ± 0.7 0.5
± 0.0 Galantamine
9.4 ± 0.7 0.5 ± 0.0
hydrobromide
structural features. Indeed, glucosyl and galactosyl linkage to chloropurine favor the
7
formation of selective AChE inhibitors, while α-glucosyl and α-mannosyl N
ligation
to 2-acetamido-6-chloropurine favors selective BChE inhibitors.
Noteworthy, in 2021, Jasiecki etal. [92] revised and discussed the relationship
between BChE levels and iron concentration in the brain, highlighting that production of BChE by glial cells is iron-dependent. Moreover, AD patients exhibit higher
iron brain levels than healthy individuals, which contributes to the overexpression
of BChE and subsequent decrease in ACh levels[89].
Several reports indicate that increased Aβ plaque formation is observed when Aβ
is expressed in a context of increased AChE levels[93–95], with the neurotoxicity
induced by AChE-Aβ complexes being greater than when promoted by Aβ alone[96].
Regarding BChE and Aβ interactions, however, much remains unclear. Although
BChE is found in amyloid-β plaques and NFTs, its role in the amyloid hypothesis of
AD is yet not fully understood. Some studies imply that BChE has a catalytic role in
Aβ aggregation, while others point to a different scenario, where BChE is actually
able to inhibit Aβ aggregation[97, 98]. In 2012, the results of a study published by
Darvesh etal. suggested that BChE is associated with a subpopulation of Aβ deposits and could take part in AD plaque maturation[99]. On the other hand, in 2016,
Kumar etal. reported that low levels of BChE (0.02–0.004 μM–cerebrospinal fluid
concentrations in AD patients) increased the formation of Aβ42 fibrils by 20–30%;
yet, higher concentrations (0.2 μM) of BChE attenuated the kinetics of amyloid-β
fibrillization process [100]. Furthermore, when present simultaneously with
10 Carbohydrates and Carbohydrate-Based Therapeutics in Alzheimer’s Disease
330
apolipoprotein E4 (ApoE4), highly stable and soluble complexes between Aβ and
BChE are formed (BAβACs), leading to a reduction in Aβ amyloid aggregation[100].
Also, it seems that Aβ interacts with a presumed activation site in the catalytic tunnel of BChE, which results in an increased ACh influx to the catalytic site, with a
consequent increase in the rate of ACh hydrolysis[100]. Altogether, these data suggest that further studies are required, aiming to clarify the role of BChE in Aβ aggregation processes.
10.6 Fyn Kinase Inhibitors
Fyn kinase, a member of the Sec family of tyrosine kinases, is increasingly recognized as a promising disease-modifying therapeutic target against AD[11]. Over the
past decade, evidence has shown that soluble amyloid β oligomers (Aβo) bind to the
C
at the neuronal surface of the postsynaptic neuron, resulting in the activation
PrP
of the metabotropic glutamate receptor 5 (mGluR5), with subsequent Fyn kinase
phosphorylation, followed by phosphorylation of downstream substrates, including
the tau protein. Chronic exposure to soluble Aβo hence contributes to the accumulation of hyperphosphorylated Tau, which composes the NFTs responsible for synaptic dysfunction in the brain of AD patients. What’s more, Fyn kinase can also
phosphorylate tau directly. By taking part in this signaling pathway, Fyn arises as a
unique linker of the two major hallmarks of AD pathology[11] (Figure10.8).
APP is sequentially cleaved by BACE-1, and γ-gamma secretase, to produce Aβ
monomers, including Aβ1–40 and Aβ1–42, at the surface of the postsynaptic neuronal membrane. These monomers aggregate into oligomers, which in turn bind to
C
PrP
APP
BACE-1
γ-Secretase
Aβ Monomers
Phosphorylation of
downstream signalling
molecules
P
P
P
P
P
P
P
P
P
P
P
P
hyperphosphorylated
Tau
Aβo
NMDA
NR2B
P
2+
Ca
Synaptic dysfunction
Fyn
mGluR5
Postsynaptic neuron - CYTOPLASM
P
EXTRACELLULAR
Figure10.8 Simplified illustration of Aβo-induced Fyn activation leading to Tau
hyperphosphorylation.
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