In Alzheimer's disease (AD) and other tauopathies, the tau protein forms fibrils, which are believed to be neurotoxic. However, fibrillar tau has been dissociated from neuron death and network dysfunction, suggesting the involvement of nonfibrillar species. Here we describe a novel pathological process in which caspase-2 cleavage of tau at Asp314 impairs cognitive and synaptic function in animal and cellular models of tauopathies by promoting the missorting of tau to dendritic spines. The truncation product, Δtau314, resists fibrillation and is present at higher levels in brains from cognitively impaired mice and humans with AD. The expression of tau mutants that resisted caspase-2 cleavage prevented tau from infiltrating spines, dislocating glutamate receptors and impairing synaptic function in cultured neurons, and it prevented memory deficits and neurodegeneration in mice. Decreasing the levels of caspase-2 restored long-term memory in mice that had existing deficits. Our results suggest an overall treatment strategy for re-establishing synaptic function and restoring memory in patients with AD by preventing tau from accumulating in dendritic spines.

Loss-of-function of the lysosomal enzyme galactosyl-ceramidase (GALC) causes the accumulation of the lipid raft-associated sphingolipid psychosine, the disruption of postnatal myelination, neurodegeneration and early death in most cases of infantile Krabbe disease. This work presents a first study towards understanding the progression of axonal defects in this disease using the Twitcher mutant mouse. Axonal swellings were detected in axons within the mutant spinal cord as early as one week after birth. As the disease progressed, more axonopathic profiles were found in other regions of the nervous system, including peripheral nerves and various brain areas. Isolated mutant neurons recapitulated axonal and neuronal defects in the absence of mutant myelinating glia, suggesting an autonomous neuronal defect. Psychosine was sufficient to induce axonal defects and cell death in cultures of acutely isolated neurons. Interestigly, axonopathy in young Twitcher mice occured in the absence of demyelination and of neuronal apoptosis. Neuronal damage occurred at later stages, when mutant mice were moribund and demyelinated. Altogether, these findings suggest a progressive dying-back neuronal dysfunction in Twitcher mutants.

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Demyelination is a major contributor to the general decay of neural functions in children with Krabbe disease. However, recent reports have indicated a significant involvement of neurons and axons in the neuropathology of the disease. In this study, we have investigated the nature of cellular inclusions in the Krabbe brain. Brain samples from the Twitcher mouse model for Krabbe disease and from patients affected with the infantile and late onset forms of the disease were examined for the presence of neuronal inclusions. Our experiments demonstrated the presence of cytoplasmic aggregates of thioflavin-S reactive material in both human and murine mutant brains. Most of these inclusions were associated with neurons. A few inclusions were detected to be associated with microglia and none were associated with astrocytes or oligodendrocytes. Thioflavin-S reactive inclusions increased in abundance paralleling the development of neurological symptoms and distributed throughout the Twitcher brain in areas of major involvement in cognition and motor functions. Electron microscopy confirmed the presence of aggregates of stereotypic β-sheet folded proteinaceous material. Immunochemical analyses identified the presence of aggregated forms of α-synuclein and ubiquitin, proteins involved in the formation of Lewy bodies in Parkinson’s disease and other neurodegenerative conditions. In vitro assays demonstrated that psychosine, the neurotoxic sphingolipid accumulated in Krabbe disease, accelerated the fibrillization of α-synuclein. This study demonstrates the occurrence of neuronal deposits of fibrillizated proteins including α-synuclein, identifying Krabbe disease as a new α-synucleinopathy.

Loss of function of galactosylceramidase lysosomal activity causes demyelination and vulnerability of various neuronal populations in Krabbe disease. Psychosine, a lipid-raft-associated sphingolipid that accumulates in this disease, is thought to trigger these abnormalities. Myelin-free in vitro analyses showed that psychosine inhibited fast axonal transport through the activation of axonal PP1 and GSK3␤ in the axon. Abnormal levels of activated GSK3␤ and abnormally phosphorylated kinesin light chains were found in nerve samples from a mouse model of Krabbe disease. Administration of GSK3␤ inhibitors significantly ameliorated transport defects in vitro and in vivo in peripheral axons of the mutant mouse. This study identifies psychosine as a pathogenic sphingolipid able to block fast axonal transport and is the first to provide a molecular mechanism underlying dying-back degeneration in this genetic leukodystrophy.

Advanced composite shells that may offer the potential to improve the structural performance of future aircraft fuselage structures were developed under this joint NASAindustry collaborative effort. Two cylindrical shells with tailored, tow-steered layups and continuously varying fiber angle orientations were designed and built at the National Center for Advanced Manufacturing -Louisiana Partnership. The shells were fabricated from unidirectional IM7/8552 graphite-epoxy pre-preg slit tape material fiber-placed on a constant-diameter mandrel. Each shell had the same nominal 8-ply [±45/±Θ] s layup, where the nominal fiber angle Θ in the tow-steered plies varied continuously from 10 degrees along the crown to 45 degrees on each side, then back to 10 degrees on the keel. One shell was fabricated with all 24 tows placed during each pass of the fiber placement machine, resulting in many tow overlaps on the shell surface. The fiber placement machine's individual tow cut/restart capability was also used to manufacture a second shell with tow drops and a more uniform laminate thickness. This paper presents an overview of the detailed design and manufacturing processes for these shells, and discusses issues encountered during their fabrication and post-cure evaluation. Future plans for structural testing and analyses of the shells are also discussed.

We compared lower limb coronal alignment measurements obtained pre- and post-operatively with long-leg radiographs and computer navigation in patients undergoing primary total knee replacement (TKR). A series of 185 patients had their pre- and post-implant radiological and computer-navigation system measurements of coronal alignment compared using the Bland-Altman method. The study included 81 men and 104 women with a mean age of 68.5 years (32 to 87) and a mean body mass index of 31.7 kg/m(2) (19 to 49). Pre-implant Bland-Altman limits of agreement were -9.4° to 8.6° with a repeatability coefficient of 9.0°. The Bland-Altman plot showed a tendency for the radiological measurement to indicate a higher level of pre-operative deformity than the corresponding navigation measurement. Post-implant limits of agreement were -5.0° to 5.4° with a repeatability coefficient of 5.2°. The tendency for valgus knees to have greater deformity on the radiograph was still seen, but was weaker for varus knees. The alignment seen or measured intra-operatively during TKR is not necessarily the same as the deformity seen on a standing long-leg radiograph either pre- or post-operatively. Further investigation into the effect of weight-bearing and surgical exposure of the joint on the mechanical femorotibial angle is required to enable the most appropriate intra-operative alignment to be selected.

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