Critical Role of PI3K/Akt/GSK3β in Motoneuron Specification from Human Neural Stem Cells in Response to FGF2 and EGF

Fibroblast growth factor (FGF) and epidermal growth factor (EGF) are critical for the development of the nervous system. We previously discovered that FGF2 and EGF had opposite effects on motor neuron differentiation from human fetal neural stem cells (hNSCs), but the underlying mechanisms remain unclear. Here, we show that FGF2 and EGF differentially affect the temporal patterns of Akt and glycogen synthase kinase 3 beta (GSK3β) activation. High levels of phosphatidylinositol 3-kinase (PI3K)/Akt activation accompanied with GSK3β inactivation result in reduction of the motor neuron transcription factor HB9. Inhibition of PI3K/Akt by chemical inhibitors or RNA interference or overexpression of a constitutively active form of GSK3β enhances HB9 expression. Consequently, PI3K inhibition increases hNSCs differentiation into HB9+/microtubule-associated protein 2 (MAP2)+ motor neurons in vitro. More importantly, blocking PI3K not only enhances motor neuron differentiation from hNSCs grafted into the ventral horn of adult rat spinal cords, but also permits ectopic generation of motor neurons in the dorsal horn by overriding environmental influences. Our data suggest that FGF2 and EGF affect the motor neuron fate decision in hNSCs differently through a fine tuning of the PI3K/AKT/GSK3β pathway, and that manipulation of this pathway can enhance motor neuron generation

Serum programmed cell death proteins in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a multifactorial, multisystem pro-inflammatory neuromuscular disorder. Activation of programmed cell death-1 (PD-1), and its ligands, programmed cell death-ligand 1 and 2 (PD-L1/L2), leads to immune suppression. Serum soluble forms of these proteins, sPD-1/sPD-L1/sPD-L2, inhibit this suppression and promote pro-inflammatory responses. The purpose of this study was to determine if sPD-1, sPD-L1, and sPD-L2 were increased in sera of patients with ALS. sPD-1 and sPD-L2 were elevated in sera of patients and accurately reflected patients’ disease burdens. Increased sera levels of programmed cell death proteins reinforce the concept that peripheral pro-inflammatory responses contribute to systemic inflammation in patients with ALS

Functional alterations of myeloid cells during the course of Alzheimer’s disease

Abstract Background Neuroinflammation is a hallmark of neurodegenerative disease and a significant component of the pathology of Alzheimer’s disease (AD). Patients present with extensive microgliosis along with elevated pro-inflammatory signaling in the central nervous system and periphery. However, the role of peripheral myeloid cells in mediating and influencing AD pathogenesis remains unresolved. Methods Peripheral myeloid cells were isolated from peripheral blood of patients with prodromal AD (n = 44), mild AD dementia (n = 25), moderate/severe AD dementia (n = 28), and age-matched controls (n = 54). Patients were evaluated in the clinic for AD severity and categorized using Clinical Dementia Rating (CDR) scale resulting in separation of patients into prodromal AD (CDR0.5) and advancing forms of AD dementia (mild-CDR1 and moderate/severe-CDR2/3). Separation of peripheral myeloid cells into mature monocytes or immature MDSCs permitted the delineation of population changes from flow cytometric analysis, RNA phenotype analysis, and functional studies using T cell suppression assays and monocyte suppression assays. Results During stages of AD dementia (CDR1 and 2/3) peripheral myeloid cells increase their pro-inflammatory gene expression while at early stages of disease (prodromal AD—CDR0.5) pro-inflammatory gene expression is decreased. MDSCs are increased in prodromal AD compared with controls (16.81% vs 9.53%) and have markedly increased suppressive functions: 42.4% suppression of activated monocyte-produced IL-6 and 78.16% suppression of T cell proliferation. In AD dementia, MDSC populations are reduced with decreased suppression of monocyte IL-6 (5.22%) and T cell proliferation (37.61%); the reduced suppression coincides with increased pro-inflammatory signaling in AD dementia monocytes. Conclusions Peripheral monocyte gene expression is pro-inflammatory throughout the course of AD, except at the earliest, prodromal stages when pro-inflammatory gene expression is suppressed. This monocyte biphasic response is associated with increased numbers and suppressive functions of MDSCs during the early stages and decreased numbers and suppressive functions in later stages of disease. Prolonging the early protective suppression and reversing the later loss of suppressive activity may offer a novel therapeutic strategy