Repetitive head trauma and apoE4 induce chronic cerebrovascular alterations that impair tau elimination from the brain.

Repetitive mild traumatic brain injuries (r-mTBI) sustained in the military or contact sports have been associated with the accumulation of extracellular tau in the brain, which may contribute to the pathogenesis of neurodegenerative tauopathies. The expression of the apolipoprotein E4 (apoE4) isoform has been associated with higher levels of tau in the brain, and worse clinical outcomes after r-mTBI, though the influence of apoE genotype on extracellular tau dynamics in the brain is poorly understood. We recently demonstrated that extracellular tau can be eliminated across blood-brain barrier (BBB), which is progressively impaired following r-mTBI. The current studies investigated the influence of repetitive mild TBI (r-mTBI) and apoE genotype on the elimination of extracellular solutes from the brain. Following intracortical injection of biotin-labeled tau into humanized apoE-Tr mice, the levels of exogenous tau residing in the brain of apoE4 mice were elevated compared to other isoforms, indicating reduced tau elimination. Additionally, we found exposure to r-mTBI increased tau residence in apoE2 mice, similar to our observations in E2FAD animals. Each of these findings may be the result of diminished tau efflux via LRP1 at the BBB, as LRP1 inhibition significantly reduced tau uptake in endothelial cells and decreased tau transit across an in vitro model of the BBB (basolateral-to-apical). Notably, we showed that injury and apoE status, (particularly apoE4) resulted in chronic alterations in BBB integrity, pericyte coverage, and AQP4 polarization. These aberrations coincided with an atypical reactive astrocytic gene signature indicative of diminished CSF-ISF exchange. Our work found that CSF movement was reduced in the chronic phase following r-mTBI (>18 months post injury) across all apoE genotypes. In summary, we show that apoE genotype strongly influences cerebrovascular homeostasis, which can lead to age-dependent deficiencies in the elimination of toxic proteins from the brain, like tau, particularly in the aftermath of head trauma.

Biomimetic Materials and Their Utility in Modeling the 3-Dimensional Neural Environment.

The brain is a complex 3-dimensional structure, the organization of which provides a local environment that directly influences the survival, proliferation, differentiation, migration, and plasticity of neurons. To probe the effects of damage and disease on these cells, a synthetic environment is needed. Three-dimensional culturing of stem cells, neural progenitors, and neurons within fabricated biomaterials has demonstrated superior biomimetic properties over conventional 2-dimensional cultureware, offering direct recapitulation of both cell-cell and cell-extracellular matrix interactions. Within this review we address the benefits of deploying biomaterials as advanced cell culture tools capable of influencing neuronal fate and as in vitro models of the native in vivo microenvironment. We highlight recent and promising biomaterials approaches toward understanding neural network and their function relevant to neurodevelopment and provide our perspective on how these materials can be engineered and programmed to study both the healthy and diseased nervous system.

Engineering of Chitosan-Hydroxyapatite-Magnetite Hierarchical Scaffolds for Guided Bone Growth.

Bioabsorbable materials have received increasing attention as innovative systems for the development of osteoconductive biomaterials for bone tissue engineering. In this paper, chitosan-based composites were synthesized adding hydroxyapatite and/or magnetite in a chitosan matrix by in situ precipitation technique. Composites were characterized by optical and electron microscopy, thermogravimetric analyses (TGA), x-ray diffraction (XRD), and in vitro cell culture studies. Hydroxyapatite and magnetite were found to be homogeneously dispersed in the chitosan matrix and the composites showed superior biocompatibility and the ability to support cell attachment and proliferation; in particular, the chitosan/hydroxyapatite/magnetite composite (CS/HA/MGN) demonstrated superior bioactivity with respect to pure chitosan (CS) and to the chitosan/hydroxyapatite (CS/HA) scaffolds.