Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes.

Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with α-synuclein (α-syn) fibrils and their clearance. We found that microglia exposed to α-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer α-syn from overloaded microglia to neighboring naive microglia where the α-syn cargo got rapidly and effectively degraded. Lowering the α-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of α-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an "on-demand" functional network in order to improve pathogenic α-syn clearance.

Systemic inflammation impairs microglial Aß clearance through NLRP3 inflammasome.

Alzheimer's disease is the most prevalent type of dementia and is caused by the deposition of extracellular amyloid-beta and abnormal tau phosphorylation. Neuroinflammation has emerged as an additional pathological component. Microglia, representing the brain's major innate immune cells, play an important role during Alzheimer's. Once activated, microglia show changes in their morphology, characterized by a retraction of cell processes. Systemic inflammation is known to increase the risk for cognitive decline in human neurogenerative diseases including Alzheimer's. Here, we assess for the first time microglial changes upon a peripheral immune challenge in the context of aging and Alzheimer's in vivo, using 2-photon laser scanning microscopy. Microglia were monitored at 2 and 10 days post-challenge by lipopolysaccharide. Microglia exhibited a reduction in the number of branches and the area covered at 2 days, a phenomenon that resolved at 10 days. Systemic inflammation reduced microglial clearance of amyloid-beta in APP/PS1 mice. NLRP3 inflammasome knockout blocked many of the observed microglial changes upon lipopolysaccharide, including alterations in microglial morphology and amyloid pathology. NLRP3 inhibition may thus represent a novel therapeutic target that may protect the brain from toxic peripheral inflammation during systemic infection.

Characterization of the secretome of human tooth germ stem cells (hTGSCs) reveals neuro-protection by fine-tuning micro-environment.

Bone-marrow-derived mesenchymal stem cells (MSCs) demonstrate neuro-protective effects in several disease models. By producing growth-factors, cytokines and chemokines, they promote survival of neurons in damaged brain areas. Alternative MSC sources, such as human tooth germ stem cells (hTGSCs), have been investigated for their neuro-protective properties. They ameliorate effects of neuro-toxic agents by paracrine mechanisms, however these secreted bio-active molecules are not yet characterized. Therefore, the current study aimed to provide a detailed analysis of the secretome of hTGSCs. Brain cells were exposed to various toxic materials, including Alzheimer's ß-amyloid peptide (ß-AP) and 6-hydroxy-dopamine (6-OHDA). When co-cultured with hTGSCs, the activity of a number of anti-oxidant enzymes (catalase, glutathione-s-transferase, glutathione-peroxidase, superoxide-dismutase) was increased and neuronal death/apoptosis was subsequently reduced. The composition of the secreted bio-active materials is influenced by various pre-existing factors such as oxygen and glucose deprivation and the age of cells (passage number). This report reveals for the first time that the neuro-protective secretome of hTGSCs and the micro-environment of cells have a mutual and dynamic impact on one another.

The Contribution of the Locus Coeruleus-Noradrenaline System Degeneration during the Progression of Alzheimer's Disease.

Alzheimer's disease (AD), which is characterized by extracellular accumulation of amyloid-beta peptide and intracellular aggregation of hyperphosphorylated tau, is the most common form of dementia. Memory loss, cognitive decline and disorientation are the ultimate consequences of neuronal death, synapse loss and neuroinflammation in AD. In general, there are many brain regions affected but neuronal loss in the locus coeruleus (LC) is one of the earliest indicators of neurodegeneration in AD. Since the LC is the main source of noradrenaline (NA) in the brain, degeneration of the LC in AD leads to decreased NA levels, causing increased neuroinflammation, enhanced amyloid and tau burden, decreased phagocytosis and impairment in cognition and long-term synaptic plasticity. In this review, we summarized current findings on the locus coeruleus-noradrenaline system and consequences of its dysfunction which is now recognized as an important contributor to AD progression.

Differentiation and neuro-protective properties of immortalized human tooth germ stem cells.

Stem cells are considered to be promising therapeutic options in many neuro-degenerative diseases and injuries to the central nervous system, including brain ischemia and spinal cord trauma. Apart from the gold standard embryonic and mesenchymal origin, human tooth germ stem cells (hTGSCs) have also been shown to enjoy the characteristics of mesenchymal stem cells (MSCs) and the ability to differentiate into adipo-, chondro-, osteo- and neuro-genic cells, suggesting that they might serve as potential alternatives in the cellular therapy of various maladies. Immortalization of stem cells may be useful to avoid senescence of stem cells and to increase their proliferation potential without altering their natural characteristics. This study evaluated the expression of stem cell markers, surface antigens, differentiation capacity, and karyotype of hTGSCs that have been immortalized by human telomerase reverse transcriptase (hTERT) or simian vacuolating virus 40 (SV40) large T antigen. These undying cells were also evaluated for their neuro-protective potential using an in vitro SH-SY5Y neuro-blastoma model treated with hydrogen-peroxide or doxo-rubicin. Although hTGSC-SV40 showed abnormal karyotypes, our results suggest that hTGSC-hTERT preserve their MSC characteristics, differentiation capacity and normal karyotype, and they also possess high proliferation rate and neuro-protective effects even at great passage numbers. These peculiars indicate that hTGSC-hTERT could be used as a viable model for studying adipo-, osteo-, odonto- and neuro-genesis, as well as neuro-protection of MSCs, which may serve as a springboard for potentially utilizing dental waste material in cellular therapy.