Abstract
Neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1β expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.
Highlights
Neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment
We investigated the therapeutic outcomes of treatment with a purine derivative drugs (PDDs), which has a tertiary amine on the N6 position, PDD005, for cognitive deficit rescue in aging mice and tau pathology treatment
After demonstrating the integrity of the endothelial cell monolayer in the co-culture, we investigated the ability of PDD005 to cross the endothelial layer into the basal compartment, which is indicative of transport across the blood-brain barrier (BBB) into the brain
Summary
Neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We assessed cognitive deficits in aging WT mice with PDD005-treatment (i.p. 3 mg/kg/day for 28 days), compared www.nature.com/scientificreports to vehicle treatment (controls) using the T-maze test (Fig. 2A). When considering the potential involvement of hippocampal neurogenesis in the pathogenesis of NDs, these results suggest that PDD005-treatment promote neurogenesis, leading to improved cognitive performance in aging mice.
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