Regeneration in the CNS is blocked by many different growth inhibitory proteins. To foster regeneration, we have investigated a strategy to block the neuronal response to growth inhibitory signals. Here, we report that injured axons regrow directly on complex inhibitory substrates when Rho GTPase is inactivated. Treatment of PC12 cells with C3 enzyme to inactivate Rho and transfection with dominant negative Rho allowed neurite growth on inhibitory substrates. Primary retinal neurons treated with C3 extended neurites on myelin-associated glycoprotein and myelin substrates. To explore regeneration in vivo, we crushed optic nerves of adult rat. After C3 treatment, numerous cut axons traversed the lesion to regrow in the distal white matter of the optic nerve. These results indicate that targeting signaling mechanisms converging to Rho stimulates axon regeneration on inhibitory CNS substrates.

Background: Tau phosphorylation affects synaptic transmission, but the underlying mechanism remains elusive. Results: NMDA receptor activation leads to phosphorylation of endogenous tau, thereby regulating the interaction of tau with Fyn and postsynaptic scaffolding protein PSD95. Conclusion: Phosphorylation of tau controls the interaction of tau with the postsynaptic PSD95-Fyn-NMDA receptor complex leading to changes in synaptic activity. Significance: The here described physiological mechanism could go awry during the development of Alzheimer disease.

It is well established that tau pathology propagates in a predictable manner in Alzheimer’s disease (AD). Moreover, tau accumulates in the cerebrospinal fluid (CSF) of AD’s patients. The mechanisms underlying the propagation of tau pathology and its accumulation in the CSF remain to be elucidated. Recent studies have reported that human tau was secreted by neurons and non-neuronal cells when it was overexpressed indicating that tau secretion could contribute to the spreading of tau pathology in the brain and could lead to its accumulation in the CSF. In the present study, we showed that the overexpression of human tau resulted in its secretion by Hela cells. The main form of tau secreted by these cells was cleaved at the C-terminal. Surprisingly, secreted tau was dephosphorylated at several sites in comparison to intracellular tau which presented a strong immunoreactivity to all phospho-dependent antibodies tested. Our data also revealed that phosphorylation and cleavage of tau favored its secretion by Hela cells. Indeed, the mimicking of phosphorylation at 12 sites known to be phosphorylated in AD enhanced tau secretion. A mutant form of tau truncated at D421, the preferential cleavage site of caspase-3, was also significantly more secreted than wild-type tau. Taken together, our results indicate that hyperphosphorylation and cleavage of tau by favoring its secretion could contribute to the propagation of tau pathology in the brain and its accumulation in the CSF.

Both anatomical and physiological mapping methods have revealed that the mammalian cerebellar cortex consists of a family of parasagittal bands of cells, each band with its own pattern of afferent and efferent axons. Monoclonal antibody mabQ113 recognizes an unknown polypeptide antigen that is confined to a subset of rat cerebellar Purkinje cells. Immunoreactive cells are arranged into parasagittal bands extending throughout the vermis and hemispheres. Expression of the Q113 epitope by individual Purkinje cells may not be all-or-nothing, since the bands tend to be more strongly stained in the vermis than the hemispheres. The band display is symmetrical about the midline and reproducible from individual to individual. Whole-mount immunocytochemistry and serial reconstruction reveal a median band of mabQ113+ Purkinje cells adjacent to the midline (P1+) and six other positive bands disposed symmetrically at either side (P2+ to P7+). Bands are distinct throughout most of the cortex but tend to fuse ventrally and caudally. There are two sources of interindividual differences. Firstly, most animals express supernumerary "satellite" bands in the vermis. Satellite bands are usually only one cell wide, are not bilaterally symmetrical, and differ in position and number from individual to individual. Secondly, the precise position of an individual band can differ, perhaps according to the variable cortical lobulation, for example, the position of P4+ in lobules VIII/IX and P6+ in lobule VII. While a scheme of parasagittal bands is a good description of the vermian organization, the distribution of mabQ113+ and mabQ113- Purkinje cells in the hemispheres may be better described as a checkerboard of antigenic patches.

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by the selective death of retinal ganglion cells (RGCs). Ocular hypertension is the most significant known risk factor for developing the disease, but the mechanism by which elevated pressure damages RGCs is currently unknown. The axonal-enriched microtubule-associated protein tau is a key mediator of neurotoxicity in Alzheimer's disease and other tauopathies. Using a well characterized in vivo rat glaucoma model, we show an age-related increase in endogenous retinal tau that was markedly exacerbated by ocular hypertension. Early alterations in tau phosphorylation, characterized by epitope-dependent hyperphosphorylation and hypophosphorylation, correlated with the appearance of tau oligomers in glaucomatous retinas. Our data demonstrate the mislocalization of tau in the somatodendritic compartment of RGCs subjected to high intraocular pressure. In contrast, tau was depleted from RGC axons in the optic nerve of glaucomatous eyes. Importantly, intraocular administration of short interfering RNA against tau effectively reduced retinal tau accumulation and promoted robust survival of RGC somas and axons, supporting a critical role for tau alterations in ocular hypertension-induced neuronal damage. Our study reveals that glaucoma displays signature pathological features of tauopathies, including tau accumulation, altered phosphorylation, and missorting; and identifies tau as a novel target to counter RGC neurodegeneration in glaucoma and prevalent optic neuropathies.