Botulinum neurotoxin A modulates the axonal release of pathological tau in hippocampal neurons.

Pathological tau aggregates propagate across functionally connected neuronal networks in human neurodegenerative pathologies, such as Alzheimer's disease. However, the mechanism underlying this process is poorly understood. Several studies have showed that tau release is dependent on neuronal activity and that pathological tau is found in the extracellular space in free form, as well as in the lumen of extracellular vesicles. We recently showed that metabotropic glutamate receptor activity and SNAP25 integrity modulate the release of pathological tau from human and mouse synaptosomes. Here, we have leveraged botulinum neurotoxins (BoNTs), which impair neurotransmitter release by cleaving specific synaptic SNARE proteins, to dissect molecular mechanisms related to tau release at synapses. In particular, we have tested the effect of botulinum neurotoxin A (BoNT/A) on the synaptic release of tau in primary mouse neurons. Hippocampal neurons were grown in microfluidic chambers and transduced with lentiviruses expressing human tau (hTau). We found that neuronal stimulation significantly increases the release of mutant hTau, whereas wild-type hTau is unaffected. Importantly, BoNT/A blocks mutant hTau release, indicating that this process is controlled by SNAP25, a component of the SNARE complex, in intact neurons. These results suggest that BoNTs are potent tools to study the spreading of pathological proteins in neurodegenerative diseases and could play a central role in identifying novel molecular targets for the development of therapeutic interventions to treat tauopathies.

Rab10 regulates the sorting of internalised TrkB for retrograde axonal transport.

Neurons process real-time information from axon terminals to coordinate gene expression, growth, and plasticity. Inputs from distal axons are encoded as a stream of endocytic organelles, termed signalling endosomes, targeted to the soma. Formation of these organelles depends on target-derived molecules, such as brain-derived neurotrophic factor (BDNF), which is recognised by TrkB receptors on the plasma membrane, endocytosed, and transported to the cell body along the microtubules network. Notwithstanding its physiological and neuropathological importance, the mechanism controlling the sorting of TrkB to signalling endosomes is currently unknown. In this work, we use primary mouse neurons to uncover the small GTPase Rab10 as critical for TrkB sorting and propagation of BDNF signalling from axon terminals to the soma. Our data demonstrate that Rab10 defines a novel membrane compartment that is rapidly mobilised towards the axon terminal upon BDNF stimulation, enabling the axon to fine-tune retrograde signalling depending on BDNF availability at the synapse. These results help clarifying the neuroprotective phenotype recently associated to Rab10 polymorphisms in Alzheimer's disease and provide a new therapeutic target to halt neurodegeneration.

The many disguises of the signalling endosome.

Neurons are highly complex and polarised cells that must overcome a series of logistic challenges to maintain homeostasis across their morphological domains. A very clear example is the propagation of neurotrophic signalling from distal axons, where target-released neurotrophins bind to their receptors and initiate signalling, towards the cell body, where nuclear and cytosolic responses are integrated. The mechanisms of propagation of neurotrophic signalling have been extensively studied and, eventually, the model of a 'signalling endosome', transporting activated receptors and associated complexes, has emerged. Nevertheless, the exact nature of this organelle remains elusive. In this Review, we examine the evidence for the retrograde transport of neurotrophins and their receptors in endosomes, outline some of their diverse physiological and pathological roles, and discuss the main interactors, morphological features and trafficking destinations of a highly flexible endosomal signalling organelle with multiple molecular signatures.