Linking astrocytes’ exosomes to Alzheimer pathogenesis and therapy

In recent years growing evidence has shown that a contagion-like mechanism underlies the progression of AD neuropathology coupled with senile plaques and NFTs. The intracerebral or peripheral inoculation with AD brain homogenate has shown the seeding of Abeta and tau does occur in primates and transgenic mice. Such findings suggested that exosomes may be involved in prion-like spreading of p-Tau-os and in processing APP. However, using human cortical astrocytes and neuron cultures, we proved that CaSR antagonists (calcilytics), like NPS 2143, do effectively suppress the overproduction and spread of the main AD drivers, Abeta-os and p-Tau-os, otherwise elicited via Abeta-42,CaSR signaling, which would prevent neuropathological spread and preserve human cortical neuronal viability and functions in vivo. Thus, given at the preclinical and amnestic minor cognitive impairment (aMCI) stages, calcilytics would stop AD progression, protecting patients’ cognitive abilities. Moreover, it is worth recalling here that exosomes are now considered to be ideal vehicles to deliver therapeutic molecules to previously inaccessible brain regions due to their ability to cross the bloodebrain barrier (BBB) bidirectionally. In CNS, perivascular astrocytes partake in the neurovascular units with brain endothelial cells, pericytes, neurons, and microglia, and by releasing and exchanging exosomes they might pick up beneficial factors that hinder AD onset/progression. In the drug discovery field, new strategies are endeavoring to engineer the exosomes as drug carriers delivering beneficial molecules/therapeutics across the BBB.