Autosomal dominant VCP hypomorph mutation impairs disaggregation of PHF-tau

Neurodegeneration in Alzheimer’s disease (AD) is closely associated with the accumulation of pathologic tau aggregates in the form of neurofibrillary tangles. We found that a p.Asp395Gly mutation in VCP (valosin-containing protein) was associated with dementia characterized neuropathologically by neuronal vacuoles and neurofibrillary tangles. Moreover, VCP appeared to exhibit tau disaggregase activity in vitro, which was impaired by the p.Asp395Gly mutation. Additionally, intracerebral microinjection of pathologic tau led to increased tau aggregates in mice in which p.Asp395Gly VCP mice was knocked in, as compared with injected wild-type mice. These findings suggest that p.Asp395Gly VCP is an autosomal-dominant genetic mutation associated with neurofibrillary degeneration in part owing to reduced tau disaggregation, raising the possibility that VCP may represent a therapeutic target for the treatment of AD.

First Human Trial of Stem Cell Transplantation in Complex Arrays for Stroke Patients Using the Intracerebral Microinjection Instrument

BACKGROUND In preclinical studies, the Intracerebral Microinjection Instrument (IMI) has demonstrated the ability to deliver therapeutics within the brain in 3-dimensional arrays from a single overlying penetration while incurring minimal localized trauma. OBJECTIVE To evaluate the safety and performance of the IMI in its first use in humans to deliver stem cells in complex configurations within brain regions affected by ischemic injury. METHODS As part of a phase 1 study, 3 chronically hemiparetic motor stroke patients received intracerebral grafts of the therapeutic stem cell line, NSI-566, using the IMI and its supporting surgical planning software. The patients were 37 to 54 yr old, had ischemic strokes more than 1 yr prior to transplantation, and received Fugl-Meyer motor scale scores of 17-48 at screening. During a single surgical procedure, patients received several neural grafts (42 ± 3) within the peri-infarct region targeted strategically to facilitate neural repair. RESULTS The IMI enabled multiple cellular deposits to be safely placed peripheral to stroke lesions. The procedure was well tolerated, recovery was uneventful, and there occurred no subsequent complications. The IMI performed reliably throughout the procedures without evident targeting errors. One year after transplantation, all 3 subjects displayed significant clinical improvement, and imaging analysis demonstrated occupation of infarct cavities with new tissue without tumor formation. CONCLUSION IMI technology permits unprecedented numbers of injections to be tactically placed in 3-dimensional arrays safely and reliably in human subjects. This advanced methodology can optimize the benefits of novel therapeutics by enabling versatile 3-dimensional intracerebral targeting.

Impaired glucose tolerance after streptozotocin microinjection into the mediodorsal prefrontal cortex of the rat

The mediodorsal prefrontal cortex (mdPFC) is a key structure of the central glucose-monitoring (GM) neural network. Previous studies indicate that intracerebral streptozotocin (STZ) microinjection-induced destruction of local chemosensory neurons results in feeding and metabolic alterations. The present experiments aimed to examine whether STZ microinjection into the mdPFC causes metabolic deficits. To do so, glucose tolerance test (GTT) and measurements of plasma metabolites were performed in STZ-treated or control rats. Intraperitoneal D-glucose load was delivered 20 min or 4 weeks following the intracerebral microinjection of STZ or saline (acute or subacute GTT, respectively). The STZ-treated rats displayed acute glucose intolerance: at the 120th min of the test, blood glucose level of these rats was significantly higher than that of the ones in the control group. When determining the plasma level of various metabolites, 30 min following the intracerebral STZ or saline microinjection, the triglyceride concentration of the STZ-treated rats was found to be reduced compared with that of the control rats. The GM neurons of the mdPFC are suggested to be involved in the organization of complex metabolic processes by which these chemosensory cells contribute to adaptive control mechanisms of the maintenance of homeostasis.