Calcium\u27s Role as Nuanced Modulator of Cellular Physiology in the Brain

Neuroscientists studying normal brain aging, spinal cord injury, Alzheimer’s disease (AD) and other neurodegenerative diseases have focused considerable effort on carefully characterizing intracellular perturbations in calcium dynamics or levels. At the cellular level, calcium is known for controlling life and death and orchestrating most events in between. For many years, intracellular calcium has been recognized as an essential ion associated with nearly all cellular functions from cell growth to degeneration. Often the emphasis is on the negative impact of calcium dysregulation and the typical worse-case-scenario leading inevitably to cell death. However, even high amplitude calcium transients, when executed acutely can alter neuronal communication and synaptic strength in positive ways, without necessarily killing neurons. Here, we focus on the evidence that calcium has a subtle and distinctive role in shaping and controlling synaptic events that underpin neuronal communication and that these subtle changes in aging or AD may contribute to cognitive decline. We emphasize that calcium imaging in dendritic components is ultimately necessary to directly test for the presence of age- or disease-associated alterations during periods of synaptic activation

Electrophysiological and Imaging Calcium Biomarkers of Aging in Male and Female 5×FAD Mice

BACKGROUND: In animal models and tissue preparations, calcium dyshomeostasis is a biomarker of aging and Alzheimer\u27s disease that is associated with synaptic dysfunction, neuritic pruning, and dysregulated cellular processes. It is unclear, however, whether the onset of calcium dysregulation precedes, is concurrent with, or is the product of pathological cellular events (e.g., oxidation, amyloid-β production, and neuroinflammation). Further, neuronal calcium dysregulation is not always present in animal models of amyloidogenesis, questioning its reliability as a disease biomarker. OBJECTIVE: Here, we directly tested for the presence of calcium dysregulation in dorsal hippocampal neurons in male and female 5×FAD mice on a C57BL/6 genetic background using sharp electrodes coupled with Oregon-green Bapta-1 imaging. We focused on three ages that coincide with the course of amyloid deposition: 1.5, 4, and 10 months old. METHODS: Outcome variables included measures of the afterhyperpolarization, short-term synaptic plasticity, and calcium kinetics during synaptic activation. Quantitative analyses of spatial learning and memory were also conducted using the Morris water maze. Main effects of sex, age, and genotype were identified on measures of electrophysiology and calcium imaging. RESULTS: Measures of resting Oregon-green Bapta-1 fluorescence showed significant reductions in the 5×FAD group compared to controls. Deficits in spatial memory, along with increases in Aβ load, were detectable at older ages, allowing us to test for temporal associations with the onset of calcium dysregulation. CONCLUSION: Our results provide evidence that reduced, rather than elevated, neuronal calcium is identified in this 5×FAD model and suggests that this surprising result may be a novel biomarker of AD

Effects of Long-Term Pioglitazone Treatment on Peripheral and Central Markers of Aging

BACKGROUND: Thiazolidinediones (TZDs) activate peroxisome proliferator-activated receptor gamma (PPARgamma) and are used clinically to help restore peripheral insulin sensitivity in Type 2 diabetes (T2DM). Interestingly, long-term treatment of mouse models of Alzheimer\u27s disease (AD) with TZDs also has been shown to reduce several well-established brain biomarkers of AD including inflammation, oxidative stress and Abeta accumulation. While TZD\u27s actions in AD models help to elucidate the mechanisms underlying their potentially beneficial effects in AD patients, little is known about the functional consequences of TZDs in animal models of normal aging. Because aging is a common risk factor for both AD and T2DM, we investigated whether the TZD, pioglitazone could alter brain aging under non-pathological conditions. METHODS AND FINDINGS: We used the F344 rat model of aging, and monitored behavioral, electrophysiological, and molecular variables to assess the effects of pioglitazone (PIO-Actos® a TZD) on several peripheral (blood and liver) and central (hippocampal) biomarkers of aging. Starting at 3 months or 17 months of age, male rats were treated for 4-5 months with either a control or a PIO-containing diet (final dose approximately 2.3 mg/kg body weight/day). A significant reduction in the Ca2+-dependent afterhyperpolarization was seen in the aged animals, with no significant change in long-term potentiation maintenance or learning and memory performance. Blood insulin levels were unchanged with age, but significantly reduced by PIO. Finally, a combination of microarray analyses on hippocampal tissue and serum-based multiplex cytokine assays revealed that age-dependent inflammatory increases were not reversed by PIO. CONCLUSIONS: While current research efforts continue to identify the underlying processes responsible for the progressive decline in cognitive function seen during normal aging, available medical treatments are still very limited. Because TZDs have been shown to have benefits in age-related conditions such as T2DM and AD, our study was aimed at elucidating PIO\u27s potentially beneficial actions in normal aging. Using a clinically-relevant dose and delivery method, long-term PIO treatment was able to blunt several indices of aging but apparently affected neither age-related cognitive decline nor peripheral/central age-related increases in inflammatory signaling

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease

Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker

Body System Effects of a Multi-Modal Training Program Targeting Chronic, Motor Complete Thoracic Spinal Cord Injury

The safety and efficacy of pharmacological and cellular transplantation strategies are currently being evaluated in people with spinal cord injury (SCI). In studies of people with chronic SCIs, it is thought that functional recovery will be best achieved when drug or cell therapies are combined with rehabilitation protocols. However, any functional recovery attributed to the therapy may be confounded by the conditioned state of the body and by training-induced effects on neuroplasticity. For this reason, we sought to investigate the effects of a multi-modal training program on several body systems. The training program included body-weight–supported treadmill training for locomotion, circuit resistance training for upper body conditioning, functional electrical stimulation for activation of sublesional muscles, and wheelchair skills training for overall mobility. Eight participants with chronic, thoracic-level, motor-complete SCI completed the 12-week training program. After 12 weeks, upper extremity muscular strength improved significantly for all participants, and some participants experienced improvements in function, which may be explained by increased strength. Neurological function did not change. Changes in pain and spasticity were highly variable between participants. This is the first demonstration of the effect of this combination of four training modalities. However, balancing participant and study-site burden with capturing meaningful outcome measures is also an important consideration

Phase 1 Safety Trial of Autologous Human Schwann Cell Transplantation in Chronic Spinal Cord Injury

A phase 1 open-label, non-randomized clinical trial was conducted to determine feasibility and safety of autologous human Schwann cell (ahSC) transplantation accompanied by rehabilitation in participants with chronic spinal cord injury (SCI). Magnetic resonance imaging (MRI) was used to screen eligible participants to estimate an individualized volume of cell suspension to be implanted. The trial incorporated standardized multi-modal rehabilitation before and after cell delivery. Participants underwent sural nerve harvest, and ahSCs were isolated and propagated in culture. The dose of culture-expanded ahSCs injected into the chronic spinal cord lesion of each individual followed a cavity-filling volume approach. Primary outcome measures for safety and trend-toward efficacy were assessed. Two participants with American Spinal Injury Association Impairment Scale (AIS) A and two participants with incomplete chronic SCI (AIS B, C) were each enrolled in cervical and thoracic SCI cohorts (  = 8 total). All participants completed the study per protocol, and no serious adverse events related to sural nerve harvest or ahSC transplantation were reported. Urinary tract infections and skin abrasions were the most common adverse events reported. One participant experienced a 4-point improvement in motor function, a 6-point improvement in sensory function, and a 1-level improvement in neurological level of injury. Follow-up MRI in the cervical (6 months) and thoracic (24 months) cohorts revealed a reduction in cyst volume after transplantation with reduced effect over time. This phase 1 trial demonstrated the feasibility and safety of ahSC transplantation combined with a multi-modal rehabilitation protocol for participants with chronic SCI