Marc Aurel Busche

Impairments in axonal transport have been implicated in the pathogenesis of tauopathies, including frontotemporal dementia and Alzheimer’s disease, yet the underlying mechanisms and reversibility of these deficits are largely unknown. In particular, the impacts of tau mutations, phosphorylation and aggregation on axonal transport in vivo remain controversial. By using two-photon imaging of axonal transport of BDNF granules in the mouse cortex, we reveal that deficits in axonal transport arise in vivo at early stages of tau pathology, preceding tangle formation and neuronal death. Mechanistically, these impairments are caused by the enlargement of tau envelopes on microtubules, which act as functional barriers for transport. Crucially, these deficits are reversed by inhibiting MAPK p38α. Together, our work demonstrates that tau pathology causes reversible deficits in axonal transport in vivo, posing the basis for pharmacological interventions to restore the physiological flux of axonal organelles and cargoes in tauopathies.

Lymphatic vessels maintain tissue fluid homeostasis and modulate inflammation, yet their spatial organization and molecular identity in the healthy human kidney, and how these change during chronic transplant rejection, remain poorly defined. Here, we show that lymphatic capillaries initiate adjacent to cortical kidney tubules and lack smooth muscle coverage. These vessels exhibit an organ-specific molecular signature, enriched for CCL14 , DNASE1L3 , and MDK , with limited expression of canonical immune-trafficking markers found in other organ lymphatics, such as LYVE1 and CXCL8 . In allografts with chronic mixed rejection, lymphatics become disorganized and infiltrate the medulla, with their endothelial junctions remodeling from a button-like to a continuous, zipper-like, architecture. Lymphatics in rejecting kidneys localize around and interconnect tertiary lymphoid structures at different maturation stages, with altered intralymphatic and perilymphatic CD4 ⁺ T cell distribution. The infiltrating T cells express IFN-γ, which upregulates coinhibitory ligands in lymphatic endothelial cells, including PVR and LGALS9. Simultaneously, lymphatics acquire HLA class II expression and exhibit C4d deposition, consistent with alloantibody binding and complement activation. Together, these findings define the spatial and molecular features of human kidney lymphatics, revealing tolerogenic reprogramming accompanied by structural perturbations during chronic transplant rejection.

Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer’s disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here, we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ in the human brain and play a key role in promoting abnormal neuronal hyperactivity in an AD knock-in mouse model. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in the mouse model in vivo. Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.

Hyperactivity mediated by synaptotoxic β-amyloid (Aβ) oligomers is one of the earliest forms of neuronal dysfunction in Alzheimer’s disease. In the search for a preventive treatment strategy, we tested the effect of scavenging Aβ peptides before Aβ plaque formation. Using in vivo two-photon calcium imaging and SF-iGluSnFR-based glutamate imaging in hippocampal slices, we demonstrate that an Aβ binding anticalin protein (Aβ-anticalin) can suppress early neuronal hyperactivity and synaptic glutamate accumulation in the APP23xPS45 mouse model of β-amyloidosis. Our results suggest that the sole targeting of Aβ monomers is sufficient for the hyperactivity-suppressing effect of the Aβ-anticalin at early disease stages. Biochemical and neurophysiological analyses indicate that the Aβ-anticalin-dependent depletion of naturally secreted Aβ monomers interrupts their aggregation to neurotoxic oligomers and, thereby, reverses early neuronal and synaptic dysfunctions. Thus, our results suggest that Aβ monomer scavenging plays a key role in the repair of neuronal function at early stages of AD.

Reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer’s Disease (AD), but the underlying assumption that neurons are the main source of pathogenic Aβ is untested. Here we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Aβ, and play a key role in promoting abnormal neuronal hyperactivity in AD. We show that selectively suppressing oligodendrocyte Aβ production improves AD brain pathology and restores neuronal function in vivo . Our findings suggest that targeting oligodendrocyte Aβ production could be a promising therapeutic strategy for treating AD.