Prodromal Parkinson's disease and the catecholaldehyde hypothesis: Insight from olfactory bulb organotypic cultures.

Parkinson's disease (PD) is a progressive, neurodegenerative disorder with an increasing incidence, unknown etiology, and is currently incurable. Advances in understanding the pathological mechanisms at a molecular level have been slow, with little attention focused on the early prodromal phase of the disease. Consequently, the development of early-acting disease-modifying therapies has been hindered. The olfactory bulb (OB), the brain region responsible for initial processing of olfactory information, is particularly affected early in PD at both functional and molecular levels but there is little information on how the cells in this region are affected by disease. Organotypic and primary OB cultures were developed and characterized. These platforms were then used to assess the effects of 3,4-dihydroxyphenylacetylaldehyde (DOPAL), a metabolite of dopamine present in increased levels in post-mortem PD tissue and which is thought to contribute to PD pathogenesis. Our findings showed that DOPAL exposure can recapitulate many aspects of PD pathology. Oxidative stress, depolarization of mitochondrial membranes, and neurodegeneration were all induced by DOPAL addition, as were measured transcriptomic changes consistent with those reported in PD clinical studies. These olfactory models of prodromal disease lend credence to the catecholaldehyde hypothesis of PD and provide insight into the mechanisms by which the OB may be involved in disease progression.

Effects of Low-Intensity Pulsed Ultrasound-Induced Blood-Brain Barrier Opening in P301S Mice Modeling Alzheimer's Disease Tauopathies.

Alzheimer's disease (AD) is the leading cause of dementia. No treatments have led to clinically meaningful impacts. A major obstacle for peripherally administered therapeutics targeting the central nervous system is related to the blood-brain barrier (BBB). Ultrasounds associated with microbubbles have been shown to transiently and safely open the BBB. In AD mouse models, the sole BBB opening with no adjunct drugs may be sufficient to reduce lesions and mitigate cognitive decline. However, these therapeutic effects are for now mainly assessed in preclinical mouse models of amyloidosis and remain less documented in tau lesions. The aim of the present study was therefore to evaluate the effects of repeated BBB opening using low-intensity pulsed ultrasounds (LIPU) in tau transgenic P301S mice with two main readouts: tau-positive lesions and microglial cells. Our results show that LIPU-induced BBB opening does not decrease tau pathology and may even potentiate the accumulation of pathological tau in selected brain regions. In addition, LIPU-BBB opening in P301S mice strongly reduced microglia densities in brain parenchyma, suggesting an anti-inflammatory action. These results provide a baseline for future studies using LIPU-BBB opening, such as adjunct drug therapies, in animal models and in AD patients.

Micromotion Derived Fluid Shear Stress Mediates Peri-Electrode Gliosis through Mechanosensitive Ion Channels.

The development of bioelectronic neural implant technologies has advanced significantly over the past 5 years, particularly in brain-machine interfaces and electronic medicine. However, neuroelectrode-based therapies require invasive neurosurgery and can subject neural tissues to micromotion-induced mechanical shear, leading to chronic inflammation, the formation of a peri-electrode void and the deposition of reactive glial scar tissue. These structures act as physical barriers, hindering electrical signal propagation and reducing neural implant functionality. Although well documented, the mechanisms behind the initiation and progression of these processes are poorly understood. Herein, in silico analysis of micromotion-induced peri-electrode void progression and gliosis is described. Subsequently, ventral mesencephalic cells exposed to milliscale fluid shear stress in vitro exhibited increased expression of gliosis-associated proteins and overexpression of mechanosensitive ion channels PIEZO1 (piezo-type mechanosensitive ion channel component 1) and TRPA1 (transient receptor potential ankyrin 1), effects further confirmed in vivo in a rat model of peri-electrode gliosis. Furthermore, in vitro analysis indicates that chemical inhibition/activation of PIEZO1 affects fluid shear stress mediated astrocyte reactivity in a mitochondrial-dependent manner. Together, the results suggest that mechanosensitive ion channels play a major role in the development of a peri-electrode void and micromotion-induced glial scarring at the peri-electrode region.

Development of three-layer collagen scaffolds to spatially direct tissue-specific cell differentiation for enthesis repair.

Enthesis repair remains a challenging clinical indication. Herein, a three-layer scaffold composed of a tendon-like layer of collagen type I, a fibrocartilage-like layer of collagen type II and a bone-like layer of collagen type I and hydroxyapatite, was designed to recapitulate the matrix composition of the enthesis. To aid tenogenic and fibrochondrogenic differentiation, bioactive molecules were loaded in the tendon-like layer or the fibrocartilage-like layer and their effect was assessed in in vitro setting using human bone marrow derived mesenchymal stromal cells and in an ex vivo model. Seeded human bone marrow mesenchymal stromal cells infiltrated and homogeneously spread throughout the scaffold. As a response to the composition of the scaffold, cells differentiated in a localised manner towards the osteogenic lineage and, in combination with differentiation medium, towards the fibrocartilage lineage. Whilst functionalisation of the tendon-like layer did not improve tenogenic cell commitment within the time frame of this work, relevant fibrochondrogenic markers were detected in the fibrocartilage-like layer when scaffolds were functionalised with bone morphogenetic protein 2 or non-functionalised at all, in vitro and ex vivo, respectively. Altogether, our data advocate the use of compartmentalised scaffolds for the repair and regeneration of interfacial tissues, such as enthesis.

A Self-Powered Piezo-Bioelectric Device Regulates Tendon Repair-Associated Signaling Pathways through Modulation of Mechanosensitive Ion Channels.

Tendon disease constitutes an unmet clinical need and remains a critical challenge in the field of orthopaedic surgery. Innovative solutions are required to overcome the limitations of current tendon grafting approaches, and bioelectronic therapies show promise in treating musculoskeletal diseases, accelerating functional recovery through the activation of tissue regeneration-specific signaling pathways. Self-powered bioelectronic devices, particularly piezoelectric materials, represent a paradigm shift in biomedicine, negating the need for battery or external powering and complementing existing mechanotherapy to accelerate the repair processes. Here, the dynamic response of tendon cells to a piezoelectric collagen-analogue scaffold comprised of aligned nanoscale fibers made of the ferroelectric material poly(vinylidene fluoride-co-trifluoroethylene) is shown. It is demonstrated that motion-powered electromechanical stimulation of tendon tissue through piezo-bioelectric device results in ion channel modulation in vitro and regulates specific tissue regeneration signaling pathways. Finally, the potential of the piezo-bioelectronic device in modulating the progression of tendinopathy-associated processes in vivo, using a rat Achilles acute injury model is shown. This study indicates that electromechanical stimulation regulates mechanosensitive ion channel sensitivity and promotes tendon-specific over non-tenogenic tissue repair processes.

Laser-Induced Periodic Surface Structure Enhances Neuroelectrode Charge Transfer Capabilities and Modulates Astrocyte Function.

The brain machine interface (BMI) describes a group of technologies capable of communicating with excitable nervous tissue within the central nervous system (CNS). BMIs have seen major advances in recent years, but these advances have been impeded because of a temporal deterioration in the signal to noise ratio of recording electrodes following insertion into the CNS. This deterioration has been attributed to an intrinsic host tissue response, namely, reactive gliosis, which involves a complex series of immune mediators, resulting in implant encapsulation via the synthesis of pro-inflammatory signaling molecules and the recruitment of glial cells. There is a clinical need to reduce tissue encapsulation in situ and improve long-term neuroelectrode functionality. Physical modification of the electrode surface at the nanoscale could satisfy these requirements by integrating electrochemical and topographical signals to modulate neural cell behavior. In this study, commercially available platinum iridium (Pt/Ir) microelectrode probes were nanotopographically functionalized using femto/picosecond laser processing to generate laser-induced periodic surface structures (LIPSS). Three different topographies and their physical properties were assessed by scanning electron microscopy and atomic force microscopy. The electrochemical properties of these interfaces were investigated using electrochemical impedance spectroscopy and cyclic voltammetry. The in vitro response of mixed cortical cultures (embryonic rat E14/E17) was subsequently assessed by confocal microscopy, ELISA, and multiplex protein array analysis. Overall LIPSS features improved the electrochemical properties of the electrodes, promoted cell alignment, and modulated the expression of multiple ion channels involved in key neuronal functions.

Polyhydroxyalkanoate/carbon nanotube nanocomposites: flexible electrically conducting elastomers for neural applications.

AIM: Medium chain length-polyhydroxyalkanoate/multi-walled carbon nanotube (MWCNTs) nanocomposites with a range of mechanical and electrochemical properties were fabricated via assisted dispersion and solvent casting, and their suitability as neural interface biomaterials was investigated. MATERIALS & METHODS: Mechanical and electrical properties of medium chain length-polyhydroxyalkanoate/MWCNTs nanocomposite films were evaluated by tensile test and electrical impedance spectroscopy, respectively. Primary rat mesencephalic cells were seeded on the composites and quantitative immunostaining of relevant neural biomarkers, and electrical stimulation studies were performed. RESULTS: Incorporation of MWCNTs to the polymeric matrix modulated the mechanical and electrical properties of resulting composites, and promoted differential cell viability, morphology and function as a function of MWCNT concentration. CONCLUSION: This study demonstrates the feasibility of a green thermoplastic MWCNTs nanocomposite for potential use in neural interfacing applications.