BackgroundMotor neuron loss is characteristic of cervical spinal cord injury (SCI) and contributes to functional deficit.Methodology/Principal FindingsIn order to investigate the amenability of the injured adult spinal cord to motor neuron differentiation, we transplanted spinal cord injured animals with a high purity population of human motor neuron progenitors (hMNP) derived from human embryonic stem cells (hESCs). In vitro, hMNPs displayed characteristic motor neuron-specific markers, a typical electrophysiological profile, functionally innervated human or rodent muscle, and secreted physiologically active growth factors that caused neurite branching and neuronal survival. hMNP transplantation into cervical SCI sites in adult rats resulted in suppression of intracellular signaling pathways associated with SCI pathogenesis, which correlated with greater endogenous neuronal survival and neurite branching. These neurotrophic effects were accompanied by significantly enhanced performance on all parameters of the balance beam task, as compared to controls. Interestingly, hMNP transplantation resulted in survival, differentiation, and site-specific integration of hMNPs distal to the SCI site within ventral horns, but hMNPs near the SCI site reverted to a neuronal progenitor state, suggesting an environmental deficiency for neuronal maturation associated with SCI.Conclusions/SignificanceThese findings underscore the barriers imposed on neuronal differentiation of transplanted cells by the gliogenic nature of the injured spinal cord, and the physiological relevance of transplant-derived neurotrophic support to functional recovery.

Across neurodegenerative diseases, common mechanisms may reveal novel therapeutic targets based on neuronal protection, repair, or regeneration, independent of etiology or site of disease pathology. To address these mechanisms and discuss emerging treatments, in April, 2021, Glaucoma Research Foundation, BrightFocus Foundation, and the Melza M. and Frank Theodore Barr Foundation collaborated to bring together key opinion leaders and experts in the field of neurodegenerative disease for a virtual meeting titled “Solving Neurodegeneration”. This “think-tank” style meeting focused on uncovering common mechanistic roots of neurodegenerative disease and promising targets for new treatments, catalyzed by the goal of finding new treatments for glaucoma, the world’s leading cause of irreversible blindness and the common interest of the three hosting foundations. Glaucoma, which causes vision loss through degeneration of the optic nerve, likely shares early cellular and molecular events with other neurodegenerative diseases of the central nervous system. Here we discuss major areas of mechanistic overlap between neurodegenerative diseases of the central nervous system: neuroinflammation, bioenergetics and metabolism, genetic contributions, and neurovascular interactions. We summarize important discussion points with emphasis on the research areas that are most innovative and promising in the treatment of neurodegeneration yet require further development. The research that is highlighted provides unique opportunities for collaboration that will lead to efforts in preventing neurodegeneration and ultimately vision loss.

Motor neuron loss is characteristic of many neurodegenerative disorders and results in rapid loss of muscle control, paralysis, and eventual death in severe cases. In order to investigate the neurotrophic effects of a motor neuron lineage graft, we transplanted human embryonic stem cell-derived motor neuron progenitors (hMNPs) and examined their histopathological effect in three animal models of motor neuron loss. Specifically, we transplanted hMNPs into rodent models of SMA (Δ7SMN), ALS (SOD1 G93A), and spinal cord injury (SCI). The transplanted cells survived and differentiated in all models. In addition, we have also found that hMNPs secrete physiologically active growth factors in vivo, including NGF and NT-3, which significantly enhanced the number of spared endogenous neurons in all three animal models. The ability to maintain dying motor neurons by delivering motor neuron-specific neurotrophic support represents a powerful treatment strategy for diseases characterized by motor neuron loss.

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The availability of human neuronal progenitors (hNPs) in high purity would greatly facilitate neuronal drug discovery and developmental studies, as well as cell replacement strategies for neurodegenerative diseases and conditions, such as spinal cord injury, stroke, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Here we describe for the first time a method for producing hNPs in large quantity and high purity from human embryonic stem cells (hESCs) in feeder-free conditions, without the use of exogenous noggin, sonic hedgehog or analogs, rendering the process clinically compliant. The resulting population displays characteristic neuronal-specific markers. When allowed to spontaneously differentiate into neuronal subtypes in vitro, cholinergic, serotonergic, dopaminergic and/or noradrenergic, and medium spiny striatal neurons were observed. When transplanted into the injured spinal cord the hNPs survived, integrated into host tissue, and matured into a variety of neuronal subtypes. Our method of deriving neuronal progenitors from hESCs renders the process amenable to therapeutic and commercial use.

Retinoic acid (RA), a metabolite of vitamin A, has many physiological functions, and mounting evidence points to important roles in cognition. In vitro experiments indicate that RA is involved in homeostatic synaptic scaling in the hippocampus, which supports overall network stability during learning. It has been previously determined that disrupted RA signaling in the hippocampus causes deterioration of memory, that RA signaling declines with age in brain, and that application of RA reverses this decline. Here, we explore whether RA signaling is altered in an animal model of neurocognitive aging. We used a Morris water maze protocol to study cognitive decline in aged rats, which assesses hippocampus-dependent spatial memory and reveals substantial interindividual differences in aged animals. Aged unimpaired (AU) rats perform on par with young (Y), while aged impaired (AI) animals exhibit spatial memory deficits. We show that the major substrate for RA, retinol binding protein 4 (RBP4), is decreased in AU rats, and retinol cell surface receptor declines with chronological age. Other affected components of RA signaling include selective increases in AI animals in hippocampal synthesis (RALDH1) and catabolism of RA (CYP26B1), RA receptor α, the RA regulated ionotropic glutamate receptor (GluR1), as well as fragile X mental retardation protein (FMRP). The results support the conclusion that, surprisingly, increased RA signaling in the aged hippocampus is associated with poor cognitive outcome.

Denervation of the piriform cortex by bulbotomy causes a series of important cellular changes in the inhibitory interneurons of layer I and transsynaptic apoptosis of a large number of pyramidal neurons in outer layer II within 24 h. In this study, we report that following the marked loss of neurons in outer layer II, the piriform cortex is reconstituted by the addition of newly formed neurons that restore the number to a preinjury level within 30 days. We provide evidence that the number of newly divided neuronal progenitors increases after injury and further show that a population of doublecortin-positive cells that resides in the piriform cortex decreases after injury. Taken together, these findings suggest that the piriform cortex has significant neurogenic potential that is activated following sensory denervation and may contribute toward the replacement of neurons in outer layer II.

Cognitive aging varies tremendously across individuals and is often accompanied by regionally specific reductions in gray matter (GM) volume, even in the absence of disease. Rhesus monkeys provide a primate model unconfounded by advanced neurodegenerative disease, and the current study used a recognition memory test (delayed non-matching to sample; DNMS) in conjunction with structural imaging and voxel-based morphometry (VBM) to characterize age-related differences in GM volume and brain-behavior relationships. Consistent with expectations from a long history of neuropsychological research, DNMS performance in young animals prominently correlated with the volume of multiple structures in the medial temporal lobe memory system. Less anticipated correlations were also observed in the cingulate and cerebellum. In aged monkeys, significant volumetric correlations with DNMS performance were largely restricted to the prefrontal cortex and striatum. Importantly, interaction effects in an omnibus analysis directly confirmed that the associations between volume and task performance in the MTL and prefrontal cortex are age-dependent. These results demonstrate that the regional distribution of GM volumes coupled with DNMS performance changes across the lifespan, consistent with the perspective that the aged primate brain retains a substantial capacity for structural reorganization.