12 Aptamers for the Diagnosis and Therapy …
355
Diagnostic Strategies Targeting Aβ
In order to develop new tools to detect Aβ, RNA aptamers were first selected by Ylera
et al. in 2002, and the dissociation constants of these aptamers were in the range of
29–48 nM [47]. The aptamer with the best affinity was named β-55 which was further
fluorescently tagged by Farrar et al. and used as optical imaging agents not only to
stain amyloid plaques ex vivo in AD brain tissue, but also to visualize plaque in
APP/PS1 transgenic mice by in vivo 2-photon imaging [48]. Then another RNA
aptamer against Aβ40 oligomer were selected by Rahimi et al. in 2009. However,
functional data showed that these aptamers had low specificity to Aβ oligomer [49].
Subsequently, a DNA aptamer named T-SO508, which can specifically recognize
and bind to Aβ oligomer, was generated in 2012. Following this study, T-SO508 was
used to set up a label-free molecular beacon system integrated with an enzyme-free
amplification strategy to quantify Aβ oligomers and monitor the Aβ aggregation
process in vitro [50]. Since these aptamers are specific for oligomers, they could be
more efficient and specific tools than antibodies in the application of recognizing the
Aβ oligomer, preventing Aβ toxicity, as well as diagnosing AD [51, 52]. Further, a
functional nucleic acid aptamer to Aβ40, called RNV95 was developed. This aptamer
could detect tetrameric/pentameric low-molecular-weight Aβ aggregates in autopsy
hippocampal tissue from two neuropathologically confirmed AD cases [53]. In addition, RNA aptamers with a higher affinity toward a toxic Aβ42 dimer were selected,
and the aptamer with the best affinity was called E22P-AbD43 [54].
Therapeutic Strategies Targeting Aβ
In order to block Aβ aggregation, firstly it is a good idea to reduce the production
of Aβ. As is known to all, the generation of Aβ is triggered by BACE1(β-site APP
cleaving enzyme-1), then BACE1 should be a worthy target of the interference of
Aβ production and treatment of AD [55]. One DNA aptamer, called A1 selected by
Liang et al., could bind to BACE1 with high affinity and good specificity. A1 was
able to not only inhibit BACE1 activity in vitro, but also decrease the production
of Aβ40 and Aβ42 secreted by M17 human neuroblastoma cells stably expressed
mutant APP [56]. To be more precise, RNA aptamers against a short cytoplasmic
tail (B1-CT) of BACE1 also have been selected by Rentmeister et al. in 2006. These
RNA aptamers could specifically bind to B1-CT with dissociation constants as low
as 240 nM, without affecting other important biological activities (the interaction
between B1-CT and GGA1, and the phosphorylation of B1-CT). Importantly, these
aptamers could also specifically recognize full-length BACE1 from cells [57].
Except reducing the production of Aβ, selecting and application of the aptamer
against Aβ oligomer should have great potential in alleviating its toxicity. RNA
aptamers against Aβ40 oligomer, selected by Rahimi et al. had shown its effect on
inhibiting Aβ aggregation in vitro. Transmission electron micrographs also suggested
that these aptamers could block Aβ40 fibrillation at the stage of small aggregates
in vitro [49]. E22P-AbD43, an RNA aptamer against Aβ42 dimer, could inhibit
the nucleation phase of Aβ42 dimer and also block its associated neurotoxicity in
SH-SY5Y cells [54].
355
Diagnostic Strategies Targeting Aβ
In order to develop new tools to detect Aβ, RNA aptamers were first selected by Ylera
et al. in 2002, and the dissociation constants of these aptamers were in the range of
29–48 nM [47]. The aptamer with the best affinity was named β-55 which was further
fluorescently tagged by Farrar et al. and used as optical imaging agents not only to
stain amyloid plaques ex vivo in AD brain tissue, but also to visualize plaque in
APP/PS1 transgenic mice by in vivo 2-photon imaging [48]. Then another RNA
aptamer against Aβ40 oligomer were selected by Rahimi et al. in 2009. However,
functional data showed that these aptamers had low specificity to Aβ oligomer [49].
Subsequently, a DNA aptamer named T-SO508, which can specifically recognize
and bind to Aβ oligomer, was generated in 2012. Following this study, T-SO508 was
used to set up a label-free molecular beacon system integrated with an enzyme-free
amplification strategy to quantify Aβ oligomers and monitor the Aβ aggregation
process in vitro [50]. Since these aptamers are specific for oligomers, they could be
more efficient and specific tools than antibodies in the application of recognizing the
Aβ oligomer, preventing Aβ toxicity, as well as diagnosing AD [51, 52]. Further, a
functional nucleic acid aptamer to Aβ40, called RNV95 was developed. This aptamer
could detect tetrameric/pentameric low-molecular-weight Aβ aggregates in autopsy
hippocampal tissue from two neuropathologically confirmed AD cases [53]. In addition, RNA aptamers with a higher affinity toward a toxic Aβ42 dimer were selected,
and the aptamer with the best affinity was called E22P-AbD43 [54].
Therapeutic Strategies Targeting Aβ
In order to block Aβ aggregation, firstly it is a good idea to reduce the production
of Aβ. As is known to all, the generation of Aβ is triggered by BACE1(β-site APP
cleaving enzyme-1), then BACE1 should be a worthy target of the interference of
Aβ production and treatment of AD [55]. One DNA aptamer, called A1 selected by
Liang et al., could bind to BACE1 with high affinity and good specificity. A1 was
able to not only inhibit BACE1 activity in vitro, but also decrease the production
of Aβ40 and Aβ42 secreted by M17 human neuroblastoma cells stably expressed
mutant APP [56]. To be more precise, RNA aptamers against a short cytoplasmic
tail (B1-CT) of BACE1 also have been selected by Rentmeister et al. in 2006. These
RNA aptamers could specifically bind to B1-CT with dissociation constants as low
as 240 nM, without affecting other important biological activities (the interaction
between B1-CT and GGA1, and the phosphorylation of B1-CT). Importantly, these
aptamers could also specifically recognize full-length BACE1 from cells [57].
Except reducing the production of Aβ, selecting and application of the aptamer
against Aβ oligomer should have great potential in alleviating its toxicity. RNA
aptamers against Aβ40 oligomer, selected by Rahimi et al. had shown its effect on
inhibiting Aβ aggregation in vitro. Transmission electron micrographs also suggested
that these aptamers could block Aβ40 fibrillation at the stage of small aggregates
in vitro [49]. E22P-AbD43, an RNA aptamer against Aβ42 dimer, could inhibit
the nucleation phase of Aβ42 dimer and also block its associated neurotoxicity in
SH-SY5Y cells [54].