360
J. Qu and J. Zhang
was isolated to detect the apparition of α-syn oligomer in vitro fibrillation process.
This aptamer was used as biosensors in the techniques of gold nanoparticles-based
colorimetric assay, surface plasmon resonance (SPR) and electrochemical impedance
spectroscopy (EIS) to detect α-syn oligomers in vitro, which implied that aptamer
could potentially serve as a viable alternative for diagnosis of PD [78].
Therapeutic Strategies Targeting α-syn
Since α-syn aggregates exert toxicity to cells, it might be the therapeutic strategy of
PD to inhibit α-syn aggregation. In our group, two DNA aptamers with a high binding
affinity (K d values in the nanomolar range) and good specificity to α-syn monomers
were selected. Both aptamers could effectively reduce α-syn aggregation in vitro and
in cells, and subsequently target the α-syn to intracellular degradation through the
lysosomal pathway. These effects consequently rescued the mitochondrial dysfunction and cellular defects caused by α-syn overexpression [79]. Subsequently, we
further investigated the in vivo effect of these aptamers on the neuropathological
deficits associated with PD. For efficient delivery of the aptamers into the mouse
brain, we employed modified exosomes with the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface. Functionally, the aptamer significantly reduced the α-syn preformed fibril (PFF)-induced pathological aggregates, and
rescued synaptic protein loss and neuronal death. Moreover, intraperitoneal administration of these aptamers-loaded RVG-exosomes into the mice with an intrastriatal
injection of α-syn PFF reduced the pathological α-syn aggregates and rescued motor
impairments [80]. So, our study first demonstrated that aptamers could be successfully delivered into the central nervous system and reduce the accumulation of α-syn
in vivo.
Furthermore, it was demonstrated that the peptide derived from β-synuclein (βsyn) protein, called β-syn36, could bind to α-syn and inhibit its aggregation [81].
Consequently, this peptide could reduce α-syn amyloid fibril and soluble oligomer
in vitro. In order to increase serum stability of β-syn36, a modified N-terminal
acetylated and C-terminal amidated peptide was synthesized, termed acetylated and
amidated retro-inverso β-syn36. Strikingly, administering retro-inverso β-syn36 to
a Drosophila PD model expressing A53T α-syn, could ameliorate the behavioral
defects and reduce α-syn accumulation in the brains of the flies [76]. This aptamer
also could potentially serve as an agent for the therapy of PD.
12.2.2.2 DA
Except for the presence of LBs, PD is also characterized by the selective loss of DA
in the substantia nigra [82, 83]. DA is a small molecule with the weight of 189 Da,
and it is involved in neuronal signal transduction. The loss of DA would lead to the
deregulation of basal ganglia which further causes motor symptoms and non-motor
symptoms [84]. As we all know, the concentration of DA usually ranges from 10
−8 to
10
−6 M in normal physiological conditions [85]. Accordingly, the aptamers against
J. Qu and J. Zhang
was isolated to detect the apparition of α-syn oligomer in vitro fibrillation process.
This aptamer was used as biosensors in the techniques of gold nanoparticles-based
colorimetric assay, surface plasmon resonance (SPR) and electrochemical impedance
spectroscopy (EIS) to detect α-syn oligomers in vitro, which implied that aptamer
could potentially serve as a viable alternative for diagnosis of PD [78].
Therapeutic Strategies Targeting α-syn
Since α-syn aggregates exert toxicity to cells, it might be the therapeutic strategy of
PD to inhibit α-syn aggregation. In our group, two DNA aptamers with a high binding
affinity (K d values in the nanomolar range) and good specificity to α-syn monomers
were selected. Both aptamers could effectively reduce α-syn aggregation in vitro and
in cells, and subsequently target the α-syn to intracellular degradation through the
lysosomal pathway. These effects consequently rescued the mitochondrial dysfunction and cellular defects caused by α-syn overexpression [79]. Subsequently, we
further investigated the in vivo effect of these aptamers on the neuropathological
deficits associated with PD. For efficient delivery of the aptamers into the mouse
brain, we employed modified exosomes with the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface. Functionally, the aptamer significantly reduced the α-syn preformed fibril (PFF)-induced pathological aggregates, and
rescued synaptic protein loss and neuronal death. Moreover, intraperitoneal administration of these aptamers-loaded RVG-exosomes into the mice with an intrastriatal
injection of α-syn PFF reduced the pathological α-syn aggregates and rescued motor
impairments [80]. So, our study first demonstrated that aptamers could be successfully delivered into the central nervous system and reduce the accumulation of α-syn
in vivo.
Furthermore, it was demonstrated that the peptide derived from β-synuclein (βsyn) protein, called β-syn36, could bind to α-syn and inhibit its aggregation [81].
Consequently, this peptide could reduce α-syn amyloid fibril and soluble oligomer
in vitro. In order to increase serum stability of β-syn36, a modified N-terminal
acetylated and C-terminal amidated peptide was synthesized, termed acetylated and
amidated retro-inverso β-syn36. Strikingly, administering retro-inverso β-syn36 to
a Drosophila PD model expressing A53T α-syn, could ameliorate the behavioral
defects and reduce α-syn accumulation in the brains of the flies [76]. This aptamer
also could potentially serve as an agent for the therapy of PD.
12.2.2.2 DA
Except for the presence of LBs, PD is also characterized by the selective loss of DA
in the substantia nigra [82, 83]. DA is a small molecule with the weight of 189 Da,
and it is involved in neuronal signal transduction. The loss of DA would lead to the
deregulation of basal ganglia which further causes motor symptoms and non-motor
symptoms [84]. As we all know, the concentration of DA usually ranges from 10
−8 to
10
−6 M in normal physiological conditions [85]. Accordingly, the aptamers against