The retrograde transport ability of adeno-associated virus (AAV) was first discovered in 2002. In an animal model of Alzheimer's disease, it was found that AAV could be retrogradely transported from the hippocampus to the olfactory cortex II. Later, more studies showed that AAV can undergo axonal retrograde transport. AAV can undergo retrograde transport not only in the central nervous system, but also in the peripheral nervous system. AAV can undergo axonal retrograde transport in many animals, including mice, rats, pigs, African green monkeys, marmosets, crab-eating macaques, rhesus monkeys, rabbits, etc. Choosing different AAV serotypes in different tissues can achieve better retrograde transport efficiency. In the brain, AAV serotypes 1, 2, 5, 6, 7, 8, 9, and rh10 can undergo axonal retrograde transport, among which AAV2 is the most frequently used in the brain. AAV serotypes 2 and 6 are widely used in the peripheral nervous system.
At present, many disease studies have utilized the retrograde axonal transport ability of AAV. Diseases studied by reverse AAV include amyotrophic lateral sclerosis (ALS), Alzheimer's disease, spinal cord injury (SCI), spinal muscular atrophy (SMA), traumatic brain injury, hereditary spastic paraplegia, spinal cord transection injury, spinal cord injury, Niemann-Pick disease type A, peripheral nerve injury, and inflammatory pain. By carrying the correct gene, the disease can be well treated, manifested as improvement in pathology, behavior, or prolonged survival. This means that the reverse axonal transport properties of AAV can be well used for disease treatment.
The mitochondrial permeability transition pore is a nonspecific transmembrane channel, and inhibition of mitochondrial permeability transition pore opening has been shown to reduce mitochondrial swelling, calcium overload, and axonal degeneration. In this study, an in vivo ICH mouse model was established by injecting autologous blood and oxygenated hemoglobin into the striatum of Thy1-YFP mice, in which pyramidal neurons and axons expressed yellow fluorescent protein. The researchers found that early axonal degeneration in ICH was dependent on mitochondrial swelling and mitochondrial permeability transition pore opening caused by cyclophilin D (CypD) activation. Both cyclosporin A inhibition and short hairpin RNA interference of cyclosporin D reduced mitochondrial permeability transition pore opening and mitochondrial damage. In addition, inhibition of cycloserine proteinase D and mitochondrial permeability transition pore opening protected the integrity of the corticospinal tract and alleviated motor dysfunction caused by ICH. These findings suggest that cycloserine proteinase D is a key mediator of axonal degeneration after ICH; inhibition of cycloserine proteinase D expression protects mitochondrial structure and function, further alleviating corticospinal tract damage and motor dysfunction after intracerebral hemorrhage.
Motor outcome after stroke depends on the integrity of the corticospinal tract (CST). To assess the integrity of the CST and CST-associated fine motor function after Intracerebral hemorrhage (ICH), viral retrograde tracking (AAV2/Retro-CAG-GFP) from the lumbar spinal cord and fine motor behavioral tests were performed. The number of retrogradely labeled GFP-positive corticospinal neurons in the ICHCypD–/– and ICHWT + CsA (Figure 1A and B) groups was greater than that in the ICHWT group. The slip rates in the beam walking and irregular ladder walking tests were decreased in the ICHCypD–/– and ICHWT + CsA groups at 3 days after ICH compared with those in the ICHWT group (Figure 1C and D). These results suggest that inhibition of CypD promotes the integrity of the CST and facilitates functional recovery after ICH.
Figure 1. CypD deficiency and CsA treatment protect the CST and alleviate motor dysfunction after ICH. (Yang Y, et al., 2023)
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