Researchers found that bits of tau from the protein’s microtubule-binding region can be detected in the cerebrospinal fluid. These, not phospho-tau or total tau, reflect neurofibrillary tangles in the Alzheimer’s brain.
The enzyme degrades anti-inflammatory fatty acids in the brain. Blocking it with a brain-penetrant small molecule calmed A1 astrocytes, synapse-eating microglia, and improved amyloidosis and cognition in a mouse model.
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.
Topline results suggested that the anti-inflammatory treatment stabilized cognition and function over six months. The trial did not include biomarkers.
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.
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.
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.