Electron tomography was used to view macromolecules composing active zone material (AZM) in axon terminals at mouse neuromuscular junctions. Connections of the macromolecules to each other, to calcium channels in the presynaptic membrane, and to synaptic vesicles docked on the membrane prior to fusing with it during synaptic transmission were similar to those of AZM macromolecules at frog neuromuscular junctions previously examined by electron tomography and support the hypothesis that AZM regulates vesicle docking and fusion. A species difference in the arrangement of AZM relative to docked vesicles may help account for a greater vesicle-presynaptic membrane contact area during docking and a greater probability of fusion during synaptic transmission in mouse. Certain AZM macromolecules in mouse were connected to synaptic vesicles contacting the presynaptic membrane at sites where fusion does not occur. These secondary docked vesicles had a different relationship to the membrane and AZM macromolecules than primary docked vesicles, consistent with their having a different AZM-regulated behavior.
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http://dx.doi.org/10.1002/cne.21975 | DOI Listing |
Alzheimers Dement
December 2024
Taipei Medical University, Taipei, Taiwan.
Understanding the physiological connection between platelets and brain function reveals new paradigms in neurodegenerative disease treatment. Platelets, traditionally associated with hemostasis, but also sometimes regarded as a mirror of neurons in the blood circulation, also encompass a spectrum of neurobiological roles, including neuroinflammation modulation, neurogenesis, and synaptic remodeling. These roles are primarily mediated through a rich array of bioactive molecules and extracellular vesicles (EVs), capable of traversing the blood-brain barrier.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE, DISTALZ, Lille, France.
Background: BIN1 is a major susceptibility gene for AD and BIN1 protein interacts with Tau. However, the contribution of BIN1 and its isoforms to AD pathogenesis remains unclear. We recently described that human BIN1 isoform1 (BIN1iso1) induces an accumulation of early endosome vesicles leading to neurodegeneration in Drosophila retina and that the early endosome size regulation was conserved in human induced neurons.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
CNR Institute of Neuroscience, Vedano al Lambro, Italy.
Background: We recently demonstrated that large extracellular vesicles (EVs) released by Aβ-loaded microglia and carrying Aβ (Aβ-EVs) propagate synaptic dysfunction in the mouse brain by moving at the axon surface (Gabrielli et al., Brain, 2022; Falcicchia et al., Brain Commun, 2023).
View Article and Find Full Text PDFBackground: Extracellular vesicles (EVs) carry pathogenic molecules and play a role in the disease spread, including aggregated tau proteins. The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery is responsible for the biogenesis of small EVs (exosomes), thus targeting critical ESCRT molecules can disrupt EV synthesis. We hypothesize that microglia-specific targeting of ESCRT-I molecule Tsg101 suppresses microglia-derived EV-mediated propagation of tau pathology, leading to amelioration of the disease phenotype of the tauopathy mouse model.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
CEDOC - Nova Medical School - Universidade NOVA de Lisboa, Lisboa, Portugal.
Background: Alzheimer's disease (AD), an untreatable synaptic disorder, is the most frequent cause of dementia. It is still unclear which mechanisms drive the early synapse dysfunction in the most common late-onset AD (LOAD). The second most important LOAD risk gene identified, BIN1, is an endocytic regulator.
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