Synaptic loss, which coincides with defects in synaptic proteins, is the best correlate of cognitive decline in Alzheimer´s disease (AD). Synaptic proteomes are shaped by protein transport from the neuronal soma and mRNAs delivered to synapses where they translate into protein locally: the latter mechanism is known as local protein synthesis (LPS).

LPS has been extensively studied in the nervous system in physiological contexts, but recent evidence indicates that this mechanism is deregulated in neurodegenerative diseases. In fact, diseases considered as synaptopathies, such as AD, are accompanied by alterations in the localization of mRNAs and their localized translation in axons, dendrites and synapses.  Indeed, I have found that Ab oligomers, an early pathological trigger of AD, induces LPS in isolated synapses. Additionally, LPS seems to be differentially deregulated in presynaptic cholinergic terminals of male and female AD mice, suggesting sexual dimorphism.

It is still unclear whether neuronal LPS in the central nervous system is uniquely regulated by the neurons themselves or if glia is involved in this mechanism. In peripheral nerves, mRNAs and ribosomes can be transferred from glia to neurons suggesting a regulation of neuronal LPS by glia. Our lab has observed that astrocytic extracellular vesicles (EVs) regulate local translation in axons of cultured neurons. Indeed, glial EVs contain ribosomal proteins and thus EVs might serve as a mechanism to transfer translation regulators to axons. One of my Thesis objectives is to determine if astrocytic EVs also contribute to presynaptic local translation in vivo and regulate synaptic integrity and function in AD.

More information:

• https://www.achucarro.org/laboratory/local-translation-in-neurons-and-glia/