Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimer's disease (AD) and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimer's disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimer's disease

Tau-mediated synaptic damage in Alzheimer’s disease

Synapses are the principal sites for chemical communication between neurons and are essential for performing the dynamic functions of the brain. In Alzheimer’s disease and related tauopathies, synapses are exposed to disease modified protein tau, which may cause the loss of synaptic contacts that culminate in dementia. In recent decades, structural, transcriptomic and proteomic studies suggest that Alzheimer’s disease represents a synaptic disorder. Tau neurofibrillary pathology and synaptic loss correlate well with cognitive impairment in these disorders. Moreover, regional distribution and the load of neurofibrillary lesions parallel the distribution of the synaptic loss. Several transgenic models of tauopathy expressing various forms of tau protein exhibit structural synaptic deficits. The pathological tau proteins cause the dysregulation of synaptic proteome and lead to the functional abnormalities of synaptic transmission. A large body of evidence suggests that tau protein plays a key role in the synaptic impairment of human tauopathies

Stem Cell Conditioned Medium Treatment for Canine Spinal Cord Injury: Pilot Feasibility Study

Spinal cord injury (SCI) involves nerve damage and often leads to motor, sensory and autonomic dysfunctions. In the present study, we have designed a clinical protocol to assess the feasibility of systemic delivery of allogenic canine bone marrow tissue-derived mesenchymal stem cell conditioned medium (BMMSC CM) to dogs with SCI. Four client-owned dogs with chronic SCI lasting more than six months underwent neurological and clinical evaluation, MRI imaging and blood tests before being enrolled in this study. All dogs received four intravenous infusions with canine allogenic BMMSC CM within one month. Between the infusions the dogs received comprehensive physiotherapy, which continued for three additional months. No adverse effects or complications were observed during the one, three and six months follow-up periods. Neither blood chemistry panel nor hematology profile showed any significant changes. All dogs were clinically improved as assessed using Olby locomotor scales after one, three and six months of BMMSC CM treatment. Furthermore, goniometric measurements revealed partial improvement in the range of joint motion. Bladder function improved in two disabled dogs. We conclude that multiple delivery of allogenic cell-derived conditioned medium to dogs with chronic SCI is feasible, and it might be clinically beneficial in combination with physiotherapy

Canine Bone Marrow-derived Mesenchymal Stem Cells: Genomics, Proteomics and Functional Analyses of Paracrine Factors

International audienceAdult stem cells have become prominent candidates for treating various diseases in veterinary practice. The main goal of our study was therefore to provide a comprehensive study of canine bone marrow-derived mesenchymal stem cells (BMMSC) and conditioned media, isolated from healthy adult dogs of different breeds. Under well-defined standardized isolation protocols, the multipotent differentiation and specific surface markers of BMMSC were supplemented with their gene expression, proteomic profile, and their biological function. The presented data confirm that canine BMMSC express important genes for differentiation toward osteo-, chondro-, and tendo-genic directions, but also genes associated with angiogenic, neurotrophic, and immunomodulatory properties. Furthermore, using proteome profiling, we identify for the first time the dynamic release of various bioactive molecules, such as transcription and translation factors and osteogenic, growth, angiogenic, and neurotrophic factors from canine BMMSC conditioned medium. Importantly, the relevant genes were linked to their proteins as detected in the conditioned medium and further associated with angiogenic activity in chorioallantoic membrane (CAM) assay. In this way, we show that the canine BMMSC release a variety of bioactive molecules, revealing a strong paracrine component that may possess therapeutic potential in various pathologies. However, extensive experimental or preclinical trials testing canine sources need to be performed in order to better understand their paracrine action, which may lead to novel therapeutic strategies in veterinary medicine