356
J. Qu and J. Zhang
Since Aβ oligomer is toxic, there should be definite receptors to exert its toxic role.
So it might be a good choice to block the target receptor of Aβ oligomer to mitigate
its toxic effect. It is demonstrated the normal prion protein (PrP
C ) is one of the
target receptors of Aβ oligomer, and it mediates impairment of synaptic plasticity by
binding to Aβ oligomer [58]. Studies have shown anti-PrP antibodies can prevent the
binding of Aβ oligomers to PrP
C and rescue synaptic plasticity in hippocampal slices
from oligomeric Aβ. Thus, aptamers that bind to PrP
C should have great therapeutic
potential as to AD.
12.2.1.2 Tau
In addition to amyloid plaques, aggregation of intracellular p-tau protein leading to
neurofibrillary tangles is another common pathological feature of AD. Tau protein
belongs to the family of microtubule-associated proteins and plays important roles
in the microtubule assembly and stabilization, contributing to cytoskeleton reorganization and regulation of axonal transport. In AD, aggregation of tau protein leads to
the formation of intracellular tangles and cytotoxic soluble toxic oligomers, consequently disrupting the normal neuronal functions [59, 60]. Therefore, tau protein
is also considered as one of the key elements involved in AD and as a warranted
diagnostic and therapeutic target for AD treatment (Fig. 12.1).
Diagnostic Strategies Targeting Tau
In order to develop new approaches to detect tau protein, a single-stranded DNA
sequence (K d in the range of 190–350 nM), binding to the human tau-381 and tau-410
isoforms (two known variants of tau ranging from 352 to 441 amino acids in length),
was identified by kinetic capillary electrophoresis [61]. This DNA oligonucleotide
was subsequently used in an aptamer-antibody sandwich assay for the first time to
detect tau-381 in human plasma at concentrations as low as 10 fM [62]. Additionally,
this DNA aptamer was modified by biotin to be used as aptasensors for detection of
tau protein in patients’ serum samples, and the limit of tau detection could be as low
as 0.7 pM. These proposed aptasensors not only display excellent performance with
good selectivity, stability, and reproducibility, but also allow for tau protein detection
in a complex matrix such as a fetal bovine serum, which indicates their utility in other
biological fluids for early diagnostic applications [63, 64]. Soon afterward, Samuele
et al. isolated high-affinity DNA aptamer, called aptamer 3146, directed against
the whole tau protein in only three rounds and one working day by non-SELEX
approach based on the capillary electrophoresis partitioning technique [65]. The
calculated dissociation constant values are better (13 nM for t-441 protein) than
those classically obtained by capillary electrophoresis-based SELEX (CE-SELEX),
which demonstrated that the aptamer 3146 could be promising as bio-recognition
element in the development of aptamer-based biosensors for detecting tau protein.
Since the hyper-phosphorylation of tau proteins can result in the formation of
protein aggregates and neurodegeneration, it is necessary to detect p-tau for the
diagnosis of AD. So, six DNA aptamers specific for tau at two phosphorylatable
J. Qu and J. Zhang
Since Aβ oligomer is toxic, there should be definite receptors to exert its toxic role.
So it might be a good choice to block the target receptor of Aβ oligomer to mitigate
its toxic effect. It is demonstrated the normal prion protein (PrP
C ) is one of the
target receptors of Aβ oligomer, and it mediates impairment of synaptic plasticity by
binding to Aβ oligomer [58]. Studies have shown anti-PrP antibodies can prevent the
binding of Aβ oligomers to PrP
C and rescue synaptic plasticity in hippocampal slices
from oligomeric Aβ. Thus, aptamers that bind to PrP
C should have great therapeutic
potential as to AD.
12.2.1.2 Tau
In addition to amyloid plaques, aggregation of intracellular p-tau protein leading to
neurofibrillary tangles is another common pathological feature of AD. Tau protein
belongs to the family of microtubule-associated proteins and plays important roles
in the microtubule assembly and stabilization, contributing to cytoskeleton reorganization and regulation of axonal transport. In AD, aggregation of tau protein leads to
the formation of intracellular tangles and cytotoxic soluble toxic oligomers, consequently disrupting the normal neuronal functions [59, 60]. Therefore, tau protein
is also considered as one of the key elements involved in AD and as a warranted
diagnostic and therapeutic target for AD treatment (Fig. 12.1).
Diagnostic Strategies Targeting Tau
In order to develop new approaches to detect tau protein, a single-stranded DNA
sequence (K d in the range of 190–350 nM), binding to the human tau-381 and tau-410
isoforms (two known variants of tau ranging from 352 to 441 amino acids in length),
was identified by kinetic capillary electrophoresis [61]. This DNA oligonucleotide
was subsequently used in an aptamer-antibody sandwich assay for the first time to
detect tau-381 in human plasma at concentrations as low as 10 fM [62]. Additionally,
this DNA aptamer was modified by biotin to be used as aptasensors for detection of
tau protein in patients’ serum samples, and the limit of tau detection could be as low
as 0.7 pM. These proposed aptasensors not only display excellent performance with
good selectivity, stability, and reproducibility, but also allow for tau protein detection
in a complex matrix such as a fetal bovine serum, which indicates their utility in other
biological fluids for early diagnostic applications [63, 64]. Soon afterward, Samuele
et al. isolated high-affinity DNA aptamer, called aptamer 3146, directed against
the whole tau protein in only three rounds and one working day by non-SELEX
approach based on the capillary electrophoresis partitioning technique [65]. The
calculated dissociation constant values are better (13 nM for t-441 protein) than
those classically obtained by capillary electrophoresis-based SELEX (CE-SELEX),
which demonstrated that the aptamer 3146 could be promising as bio-recognition
element in the development of aptamer-based biosensors for detecting tau protein.
Since the hyper-phosphorylation of tau proteins can result in the formation of
protein aggregates and neurodegeneration, it is necessary to detect p-tau for the
diagnosis of AD. So, six DNA aptamers specific for tau at two phosphorylatable