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bioRxiv · 10.1101/2025.07.15.664857

Impaired BDNF-TrkB trafficking and signalling in Down syndrome basal forebrain neurons

Blackburn, E.·Birsa, N.·Lazo, O. M.·Fisher, E.·Schiavo, G.
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Abstract

Brain derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) play crucial roles in neuronal development, synaptic transmission, and neuroplasticity. Deficits in BDNF/TrkB signalling and trafficking have been identified in several neurodegenerative diseases, including Alzheimers disease (AD). Individuals with Down syndrome (DS) are at an increased risk of developing AD compared to the general population. Basal forebrain neurons (BFNs) are among the first to degenerate in AD and DS, but the mechanisms underlying their vulnerability remain unclear. Using BFNs derived from the Dp1Tyb mouse model of DS, we investigated neurotrophic signalling and trafficking deficits in AD-DS. We found enlarged early endosomes and elevated levels of active Rab5, a GTPase critical for early endosome formation, in Dp1Tyb BFNs. These abnormalities were associated with impaired transport of internalised TrkB from axon terminals to the soma. Using microfluidic devices, we demonstrated that axonal BDNF stimulation enhanced signalling endosome dynamics in wild-type but not Dp1Tyb BFNs, which is likely due to impaired axonal ERK1/2 signalling. Our findings establish a link between Rab5 hyperactivation, endosomal dysfunction, and impaired ERK1/2 signalling, highlighting the interplay between trafficking and neurotrophic signalling, and underscore the importance of targeting endolysosomal and signalling pathways to mitigate neuronal dysfunction in AD-DS.

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Blackburn, E., Birsa, N., Lazo, O. M., Fisher, E., Schiavo, G.. 2025-07-18. Impaired BDNF-TrkB trafficking and signalling in Down syndrome basal forebrain neurons. https://doi.org/10.1101/2025.07.15.664857

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