By tracing the transcriptomes of neurons that wither early and late in the course of Alzheimer’s disease, researchers peg subpopulations of excitatory neurons in entorhinal cortex as selectively vulnerable to tau. Reactive astrocytes aid and abet.
In cultured cells, lysosomal activity was necessary to enable tau seeds to break out of internalized exosomes and trigger the aggregation of tau in the cytosol.
Overexpressing the endosomal activator in neurons not only caused those organelles to swell, but also bungled synaptic transmission, goaded hyperphosphorylation of tau, and destroyed cholinergic neurons.
Neurons take up extracellular vesicles containing tau oligomers more readily than they do free tau. Some gift: This speeds the march of tauopathy through mouse brain.
Topline results suggested that the anti-inflammatory treatment stabilized cognition and function over six months. The trial did not include biomarkers.
The brain shrinkage due to verubecestat emerged quickly but did not worsen or cause neurodegeneration. Curiously, both verubecestat and lanabecestat dulled episodic memory and boosted verbal fluency.