Myelin contributes to the parallel orientation of axonal growth on white matter in vitro

BACKGROUND: Brain and spinal cord white matter can support extensive axonal growth. This growth is generally constrained to an orientation that is parallel to the longitudinal axis of the fiber tract. This constraint is presumably due to permissive and non-permissive substrates that are interleaved with each other and oriented in parallel within the tract. RESULTS: Embryonic chick sympathetic neurons were cultured on cryostat sections of rat brain and the orientation of neurite growth on white matter was assessed. To determine if haptotaxis is sufficient to guide parallel neurite growth, neurons were cultured under conditions designed to interfere with interactions between growing neurites and factors that act as biochemical contact guidance cues but not interactions with haptotactic cues. Under these conditions, neurites extending on white matter were not exclusively oriented in parallel to the fiber tract, suggesting that biochemical cues are involved. To assess the role of myelin in guiding parallel neurite growth, neurons were cultured on myelin-deficient corpus callosum. These neurons also extended neurites that were not constrained to a parallel orientation. Moreover, preincubation with NGF and treatment with cAMP analogs, manipulations that attenuate overall myelin-mediated inhibition of neurite growth, also led to a reduced parallel orientation of neurite growth. CONCLUSIONS: The present studies suggest that some of the relevant factors that constrain axonal growth on white matter are not haptotactic in nature and appear to be partly mediated by factors that are associated with myelin and may involve myelin-associated "inhibitors"

Disruption of spinal cord white matter and sciatic nerve geometry inhibits axonal growth in vitro in the absence of glial scarring

BACKGROUND: Axons within the mature mammalian central nervous system fail to regenerate following injury, usually resulting in long-lasting motor and sensory deficits. Studies involving transplantation of adult neurons into white matter implicate glial scar-associated factors in regeneration failure. However, these studies cannot distinguish between the effects of these factors and disruption of the spatial organization of cells and molecular factors (disrupted geometry). Since white matter can support or inhibit neurite growth depending on the geometry of the fiber tract, the present study sought to determine whether disrupted geometry is sufficient to inhibit neurite growth. RESULTS: Embryonic chick sympathetic neurons were cultured on unfixed longitudinal cryostat sections of mature rat spinal cord or sciatic nerve that had been crushed with forceps ex vivo then immediately frozen to prevent glial scarring. Neurite growth on uncrushed portions of spinal cord white matter or sciatic nerve was extensive and highly parallel with the longitudinal axis of the fiber tract but did not extend onto crushed portions. Moreover, neurite growth from neurons attached directly to crushed white matter or nerve tissue was shorter and less parallel compared with neurite growth on uncrushed tissue. In contrast, neurite growth appeared to be unaffected by crushed spinal cord gray matter. CONCLUSIONS: These observations suggest that glial scar-associated factors are not necessary to block axonal growth at sites of injury. Disruption of fiber tract geometry, perhaps involving myelin-associated neurite-growth inhibitors, may be sufficient to pose a barrier to regenerating axons in spinal cord white matter and peripheral nerves

Down's Syndrome with Alzheimer's Disease-Like Pathology: What Can It Teach Us about the Amyloid Cascade Hypothesis?

Down's syndrome (DS, trisomy 21) represents a complex genetic abnormality that leads to pathology in later life that is similar to Alzheimer's disease (AD). We compared two cases of DS with APOE ε3/3 genotypes, a similar age at death, and comparable amyloid-beta 42 peptide (Aβ42) burdens in the brain but that differed markedly in the severity of AD-like pathology. One exhibited extensive neurofibrillary pathology whereas the other showed minimal features of this type. Comparable loads of Aβ42 could relate to the cases' similar life-time accumulation of Aβ due to trisomy 21-enhanced metabolism of amyloid precursor protein (APP). The cases' significant difference in AD-like pathology, however, suggests that parenchymal deposition of Aβ42, even when extensive, may not inevitably trigger AD-like tau pathology (though it may be necessary). Thus, these observations of a natural experiment may contribute to understanding the nuances of the amyloid cascade hypothesis of AD pathogenesis

Segregated neural explants exhibit co-oriented, asymmetric, neurite outgrowth

Explants of embryonic chick sympathetic and sensory ganglia were found to exhibit asymmetric radial outgrowth of neurites under standard culture conditions with or without exogenous Nerve Growth Factor [NGF]. Opposing sides of an explant exhibited: a) differences in neurite length and, b) differences in neurite morphology. Strikingly, this asymmetry exhibited co-orientation among segregated, neighboring explants. The underlying mechanism(s) of the asymmetry and its co-orientation are not known but appear to depend on cell clustering because dissociated sympathetic neurons do not exhibit co-orientation whereas re-aggregated clusters of cells do. This emergent behavior may be similar to the community effect described in other cell types. If a similar phenomenon exists in the embryo, or in maturity, it may contribute to the establishment of proper orientation of neurite outgrowth during development and/or injury-induced neuronal plasticity

Nerve growth factor in Alzheimer\u27s disease: Increased levels throughout the brain coupled with declines in nucleus basalis

The current study analyzed NGF protein levels in the brains of patients with Alzheimer\u27s disease (AD) as compared with aged neurologically normal individuals. An established two-site ELISA was used to measure NGF-like immunoreactivity in the hippocampus, superior temporal gyrus, superior frontal gyrus, inferior parietal lobule, frontal and occipital cortical poles, cerebellum, amygdala, putamen, and nucleus basalis of Meynert (nbM). ChAT activity was assayed in adjacent tissue samples. NGF levels were also evaluated in Parkinson\u27s disease for comparison with both AD and age-matched control cases. Regardless of the brain bank (University of Cincinnati, Rush Presbyterian St. Luke\u27s Medical Center in Chicago, or University of Alabama at Birmingham), NGF-like activity was at least moderately increased with AD in virtually every brain region examined except for the nbM, in which significant declines were observed. NGF levels were also increased when compared with age-matched Parkinson\u27s cases (frontal cortex). NGF-like activity was not related to age at onset or disease duration in AD cases, nor did NGF levels correlate with age at death in the control or AD groups. Correlations between ChAT and NGF-like activity across brains varied considerably and were generally not significant. The present findings indicate that AD is characterized by a widespread increase in cortical and subcortical NGF. Although a correlation with ChAT activity was not observed in cortex, the AD-related decline in NGF found in nbM is consistent with the possibility of impaired retrograde transport of NGF to this region