APP metabolism regulates tau proteostasis in human cerebral cortex neurons.

Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer's disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis.

Dopamine from the brain promotes spinal motor neuron generation during development and adult regeneration.

Coordinated development of brain stem and spinal target neurons is pivotal for the emergence of a precisely functioning locomotor system. Signals that match the development of these far-apart regions of the central nervous system may be redeployed during spinal cord regeneration. Here we show that descending dopaminergic projections from the brain promote motor neuron generation at the expense of V2 interneurons in the developing zebrafish spinal cord by activating the D4a receptor, which acts on the hedgehog pathway.

Lesion-induced generation of interneuron cell types in specific dorsoventral domains in the spinal cord of adult zebrafish.

In contrast to mammals, adult zebrafish regenerate neurons in the lesioned spinal cord. For example, motor neurons are generated from an olig2-expressing population of pMN-like ependymoradial glial cells in a ventrolateral position at the central canal. However, the extent of neuronal regeneration is unclear.

Notch signaling controls generation of motor neurons in the lesioned spinal cord of adult zebrafish.

In mammals, increased Notch signaling is held partly responsible for a lack of neurogenesis after a spinal injury. However, this is difficult to test in an essentially nonregenerating system. We show that in adult zebrafish, which exhibit lesion-induced neurogenesis, e.