Human-Induced Neurons from Presenilin 1 Mutant Patients Model Aspects of Alzheimer's Disease Pathology.

Traditional approaches to studying Alzheimer's disease (AD) using mouse models and cell lines have advanced our understanding of AD pathogenesis. However, with the growing divide between model systems and clinical therapeutic outcomes, the limitations of these approaches are increasingly apparent. Thus, to generate more clinically relevant systems that capture pathological cascades within human neurons, we generated human-induced neurons (HiNs) from AD and non-AD individuals to model cell autonomous disease properties. We selected an AD patient population expressing mutations in presenilin 1 (mPS1), which is linked to increased amyloid production, tau pathology, and calcium signaling abnormalities, among other features. While these AD components are detailed in model systems, they have yet to be collectively identified in human neurons. Thus, we conducted molecular, immune-based, electrophysiological, and calcium imaging studies to establish patterns of cellular pathology in this patient population. We found that mPS1 HiNs generate increased Aß42 and hyperphosphorylated tau species relative to non-AD controls, and exaggerated ER calcium responses that are normalized with ryanodine receptor (RyR) negative allosteric modulators. The inflammasome product, interleukin-18 (IL-18), also increased PS1 expression. This work highlights the potential for HiNs to model AD pathology and validates their role in defining cellular pathogenesis and their utility for therapeutic screening.

Liposaccharide-induced sustained mild inflammation fragments social behavior and alters basolateral amygdala activity.

RATIONALE: Conditions with sustained low-grade inflammation have high comorbidity with depression and anxiety and are associated with social withdrawal. The basolateral amygdala (BLA) is critical for affective and social behaviors and is sensitive to inflammatory challenges. Large systemic doses of lipopolysaccharide (LPS) initiate peripheral inflammation, increase BLA neuronal activity, and disrupt social and affective measures in rodents. However, LPS doses commonly used in behavioral studies are high enough to evoke sickness syndrome, which can confound interpretation of amygdala-associated behaviors. OBJECTIVES AND METHODS: The objectives of this study were to find a LPS dose that triggers mild peripheral inflammation but not observable sickness syndrome in adult male rats, to test the effects of sustained mild inflammation on BLA and social behaviors. To accomplish this, we administered single doses of LPS (0-100 µg/kg, intraperitoneally) and measured open field behavior, or repeated LPS (5 µg/kg, 3 consecutive days), and measured BLA neuronal firing, social interaction, and elevated plus maze behavior. RESULTS: Repeated low-dose LPS decreased BLA neuron firing rate but increased the total number of active BLA neurons. Repeated low-dose LPS also caused early disengagement during social bouts and less anogenital investigation and an overall pattern of heightened social caution associated with reduced gain of social familiarity over the course of a social session. CONCLUSIONS: These results provide evidence for parallel shifts in social interaction and amygdala activity caused by prolonged mild inflammation. This effect of inflammation may contribute to social symptoms associated with comorbid depression and chronic inflammatory conditions.

Viral tools for mapping and modulating neural networks after spinal cord injury.

Repairing the damaged neural networks in traumatic spinal cord injury presents a difficult challenge for neuroscientists. While significant progress has been made in therapeutic strategies for SCI, research is hindered by the complicated organization of the spinal cord, the diverse molecular mechanisms of neurotrauma, and the innate lack of regenerative ability of neurons. A promising therapeutic approach involves using viral strategies to promote regeneration and rewiring of the injured spinal cord. In this special issue of Experimental Neurology, Metcalf et al., demonstrates how retrogradely traveling adeno-associated virus (AAV) vectors (rAAV-retro) can be used to target multiple brain regions that synapse in the spinal cord with a single injection strategy. This study demonstrates the unique potential of rAAV-retro to simultaneously deliver genetic cargo to promote axonal regeneration in the various pathways disrupted after spinal cord injury. Future studies will further our understanding of how best to utilize these viral strategies to repair the injured spinal cord and promote functional recovery.

Calcium-Handling Defects and Neurodegenerative Disease.

Calcium signaling is critical to neuronal function and regulates highly diverse processes such as gene transcription, energy production, protein handling, and synaptic structure and function. Because there are many common underlying calcium-mediated pathological features observed across several neurological conditions, it has been proposed that neurodegenerative diseases have an upstream underlying calcium basis in their pathogenesis. With certain diseases such as Alzheimer's, Parkinson's, and Huntington's, specific sources of calcium dysregulation originating from distinct neuronal compartments or channels have been shown to have defined roles in initiating or sustaining disease mechanisms. Herein, we will review the major hallmarks of these diseases, and how they relate to calcium dysregulation. We will then discuss neuronal calcium handling throughout the neuron, with special emphasis on channels involved in neurodegeneration.