Shigemi Ishikawa-Nagai, DMD, PhD, MSD | Harvard School of Dental Medicine; John da Silva, DMD, MPH, ScM | Harvard School of Dental Medicine; Albert Galaburda, MD | Harvard Medical School and Beth Israel Deaconess Medical Center; and Masazumi Nagai, DMD, PhD | Harvard School of Dental Medicine
Competition Sponsor: National Academy of Medicine
Awardee Year: 2020
“Paradigm Shift in the Molecular Transport to Brain through the Direct Central Nerve-Innervation Based Retrograde Axonal Transport of Craniofacial Tissue Exosomes (RATCE)” Along with life expectancy, age-associated Alzheimer’s disease (AD) has been increasing. While dysfunction of the blood-brain barrier (BBB) may contribute to AD, the BBB also limits the passage of beneficial molecules. Alternative routes into the brain remain to be explored. We previously reported that masseter muscle packaged neprilysin (NEP), which breaks down amyloid b, in exosomes and sent them to hippocampus by retrograde axonal transport along trigeminal nerve, bypassing the BBB. The direct central nerve-innervation exceptionally occurs in craniofacial tissues (CFT) such as masseter/facial expression/tongue-muscle, periodontal fibroblasts, submandibular gland cells, and dental pulp stromal cells. Every CFT can also transport neuroprotective agents to the brain through RATCE. The first aim of this proposal will identify neuroprotective RATCE cargo through comparative mRNA transcriptome profiling between hippocampal neuron cells and CFT cells with glial astrocytes as positive competitor owing to their neuroprotective functions. Proteins corresponding to neuron-negligible and CFT/glial-dominant mRNA transcripts will be validated in corresponding exosomes and hippocampal neuron as the RATCE cargo. The cargo comparison between CFT and glial astrocytes will shed light on the significance of RATCE. The second aim will compare the therapeutic efficacies of RATCE with conventional intravenous and body muscle injections on AD onset in the amyloid-based disease model mice. This proposal offers a paradigm shifting innovation in the physiological maintenance of brain homeostasis and therapeutic drug delivery through the BBB-independent RATCE pathways.
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