Carnosine improves aging-induced cognitive impairment and brain regional neurodegeneration in relation to the neuropathological alterations in the secondary structure of amyloid beta (Aß).

Aging-induced proteinopathies, including deterioration of amyloid beta (Aß) conformation, are associated with reductions in endogenous levels of carnosine and cognitive impairments. Carnosine is a well-known endogenous antioxidant, which counteracts aging-induced Aß plaque formation. The aim of this study was to investigate the effects of exogenous carnosine treatments on aging-induced changes (a) in the steady-state level of endogenous carnosine and conformation of Aß secondary structure in the different brain regions (cerebral cortex, hippocampus, hypothalamus, pons-medulla, and cerebellum) and (b) cognitive function. Young (4 months) and aged (18 and 24 months) male albino Wistar rats were treated with carnosine (2.0 µg kg-1  day-1 ; i.t.) or equivalent volumes of vehicle (saline) for 21 consecutive days and were tested for cognition using 8-arm radial maze test. Brains were processed to assess the conformational integrity of Aß plaques using Raman spectroscopy and endogenous levels of carnosine were measured in the brain regions using HPLC. Results indicated that carnosine treatments improved the aging-induced deficits in cognitive function and reduced the ß-sheets in the secondary structure of Aß protein, as well as mitigating the reduction in the steady-state levels of carnosine and spine density in the brain regions examined. These results thus, suggest that carnosine can attenuate the aging-induced: (a) conformational changes in Aß secondary structure by reducing the abundance of ß-sheets and reductions in carnosine content in the brain regions and (b) cognitive impairment.

Liraglutide Has Anti-Inflammatory and Anti-Amyloid Properties in Streptozotocin-Induced and 5xFAD Mouse Models of Alzheimer's Disease.

Recent clinical and epidemiological studies support the contention that diabetes mellitus (DM) is a strong risk factor for the development of Alzheimer's disease (AD). The use of insulin cell toxin, streptozotocin (STZ), when injected into the lateral ventricles, develops an insulin resistant brain state (IRBS) and represents a non-transgenic, or sporadic AD model (SAD), with several AD-like neuropathological features. The present study explored the effects of an anti-diabetic drug, liraglutide (LIR), in reversing major pathological hallmarks in the prodromal disease stage of both the 5xFAD transgenic and SAD mouse models of AD. Three-month-old 5xFAD and age-matched wild type mice were given a single intracerebroventricular (i.c.v) injection of STZ or vehicle (saline) and were subsequently treated with LIR, intraperitoneally (IP), once a day for 30 days. The extent of neurodegeneration, Aß plaque load, and key proteins associated with the insulin signaling pathways were measured using Western blot and neuroinflammation (via immunohistological assays) in the cortical and hippocampal regions of the brain were assessed following a series of behavioral tests used to measure cognitive function after LIR or vehicle treatments. Our results indicated that STZ significantly increased neuroinflammation, Aß plaque deposition and disrupted insulin signaling pathway, while 25 nmol/kg LIR, when injected IP, significantly decreased neuroinflammatory responses in both SAD and 5xFAD mice before significant cognitive changes were observed, suggesting LIR can reduce early neuropathology markers prior to the emergence of overt memory deficits. Our results indicate that LIR has neuroprotective effects and has the potential to serve as an anti-inflammatory and anti-amyloid prophylactic therapy in the prodromal stages of AD.

Ameliorative Properties of Boronic Compounds in In Vitro and In Vivo Models of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by amyloid (Aß) aggregation, hyperphosphorylated tau, neuroinflammation, and severe memory deficits. Reports that certain boronic compounds can reduce amyloid accumulation and neuroinflammation prompted us to compare trans-2-phenyl-vinyl-boronic-acid-MIDA-ester (TPVA) and trans-beta-styryl-boronic-acid (TBSA) as treatments of deficits in in vitro and in vivo models of AD. We hypothesized that these compounds would reduce neuropathological deficits in cell-culture and animal models of AD. Using a dot-blot assay and cultured N2a cells, we observed that TBSA inhibited Aß42 aggregation and increased cell survival more effectively than did TPVA. These TBSA-induced benefits were extended to C. elegans expressing Aß42 and to the 5xFAD mouse model of AD. Oral administration of 0.5 mg/kg dose of TBSA or an equivalent amount of methylcellulose vehicle to groups of six- and 12-month-old 5xFAD or wild-type mice over a two-month period prevented recognition- and spatial-memory deficits in the novel-object recognition and Morris-water-maze memory tasks, respectively, and reduced the number of pyknotic and degenerated cells, Aß plaques, and GFAP and Iba-1 immunoreactivity in the hippocampus and cortex of these mice. These findings indicate that TBSA exerts neuroprotective properties by decreasing amyloid plaque burden and neuroinflammation, thereby preventing neuronal death and preserving memory function in the 5xFAD mice.

Solid Lipid Curcumin Particles Protect Medium Spiny Neuronal Morphology, and Reduce Learning and Memory Deficits in the YAC128 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms, accompanied by massive neuronal degeneration in the striatum. In this study, we utilized solid lipid curcumin particles (SLCPs) and solid lipid particles (SLPs) to test their efficacy in reducing deficits in YAC128 HD mice. Eleven-month-old YAC128 male and female mice were treated orally with SLCPs (100 mg/kg) or equivalent volumes of SLPs or vehicle (phosphate-buffered saline) every other day for eight weeks. Learning and memory performance was assessed using an active-avoidance task on week eight. The mice were euthanized, and their brains were processed using Golgi-Cox staining to study the morphology of medium spiny neurons (MSNs) and Western blots to quantify amounts of DARPP-32, brain-derived neurotrophic factor (BDNF), TrkB, synaptophysin, and PSD-95. We found that both SLCPs and SLPs improved learning and memory in HD mice, as measured by the active avoidance task. We also found that SLCP and SLP treatments preserved MSNs arborization and spinal density and modulated synaptic proteins. Our study shows that SLCPs, as well as the lipid particles, can have therapeutic effects in old YAC128 HD mice in terms of recovering from HD brain pathology and cognitive deficits.

Transplantation of mesenchymal stem cells overexpressing interleukin-10 induces autophagy response and promotes neuroprotection in a rat model of TBI.

Autophagy, including mitophagy, is critical for neuroprotection in traumatic brain injury (TBI). Transplantation of mesenchymal stem cells (MSCs) provides neuroprotection and induces autophagy by increasing anti-inflammatory cytokines, such as interleukin-10 (IL-10). To evaluate these effects of IL10 that are released by MSCs, we genetically engineered MSCs to overexpress IL10 and compared their effects to unaltered MSCs following transplantation near the site of induced TBIs in rats. Adult, male Sprague-Dawley rats were divided into four groups: Sham + vehicle, TBI + vehicle, TBI + MSCs-IL-10 and TBI + MSCs-GFP. Thirty-six hours post-TBI, the first two groups received vehicle (Hanks balance salt solution), whereas last two groups were transplanted with MSCs-IL-10 or MSCs-GFP. Three weeks after transplantation, biomarkers for neurodegenerative changes, autophagy, mitophagy, cell death and survival markers were measured. We observed a significant increase in the number of dead cells in the cortex and hippocampus in TBI rats, whereas transplantation of MSCs-IL-10 significantly reduced their numbers in comparison to MSCs alone. MSCs-IL-10 rats had increased autophagy, mitophagy and cell survival markers, along with decreased markers for cell death and neuroinflammation. These results suggest that transplantation of MSCs-IL-10 may be an effective strategy to protect against TBI-induced neuronal damage.

Curcumin and Solid Lipid Curcumin Particles Induce Autophagy, but Inhibit Mitophagy and the PI3K-Akt/mTOR Pathway in Cultured Glioblastoma Cells.

Autophagy and the (PI3K-Akt/mTOR) signaling pathway play significant roles in glioblastoma multiforme (GBM) cell death and survival. Curcumin (Cur) has been reported to prevent several cancers, including GBM. However, the poor solubility and limited bioavailability of natural Cur limits its application in preventing GBM growth. Previously, we have shown the greater apoptotic and anti-carcinogenic effects of solid lipid Cur particles (SLCP) than natural Cur in cultured GBM cells. Here, we compared the autophagic responses on cultured U-87MG, GL261, F98, C6-glioma, and N2a cells after treatment with Cur or SLCP (25 µM for 24 h). Different autophagy, mitophagy, and chaperone-mediated autophagy (CMA) markers, along with the PI3K-AKkt/mTOR signaling pathway, and the number of autophagy vacuoles were investigated after treatment with Cur and or SLCP. We observed increased levels of autophagy and decreased levels of mitophagy markers, along with inhibition of the PI3K-Akt/mTOR pathway after treatments with Cur or SLCP. Cell survival markers were downregulated, and cell death markers were upregulated after these treatments. We found greater effects in the case of SCLP-treated cells in comparison to Cur. Given that fewer effects were observed on C-6 glioma and N2a cells. Our results suggest that SLCP could be a safe and effective means of therapeutically modulating autophagy in GBM cells.

Solid lipid curcumin particles provide greater anti-amyloid, anti-inflammatory and neuroprotective effects than curcumin in the 5xFAD mouse model of Alzheimer's disease.

BACKGROUND: Neuroinflammation and the presence of amyloid beta protein (Aß) and neurofibrillary tangles are key pathologies in Alzheimer's disease (AD). As a potent anti-amyloid and anti-inflammatory natural polyphenol, curcumin (Cur) could be potential therapies for AD. Unfortunately, poor solubility, instability in physiological fluids, and low bioavailability limit its clinical utility. Recently, different lipid modifications in the formulae of Cur have been developed that would enhance its therapeutic potential. For example, we have reported greater permeability and neuroprotection with solid lipid curcumin particles (SLCP) than with natural Cur in an in vitro model of AD. In the present study, we compared the Aß aggregation inhibition, anti-amyloid, anti-inflammatory responses of Cur and or SLCP in both in vitro and in vivo models of AD. One-year-old 5xFAD-and age-matched wild-type mice were given intraperitoneal injections of Cur or SLCP (50 mg/kg body weight) for 2- or 5-days. Levels of Aß aggregation, including oligomers and fibril formation, were assessed by dot blot assay, while Aß plaque load and neuronal morphology in the pre-frontal cortex (PFC) and hippocampus were assayed by immunolabeling with Aß-specific antibody and cresyl violet staining, respectively. In addition, neuroinflammation was assessed the immunoreactivity (IR) of activated astrocytes (GFAP) and microglia (Iba-1) in different brain areas. Finally, comparisons of solubility and permeability of Cur and SLCP were made in cultured N2a cells and in primary hippocampal neurons derived from E16 pups of 5xFAD mice. RESULTS: We observed that relative to Cur, SLCP was more permeable, labeled Aß plaques more effectively, and produced a larger decrease in Aß plaque loads in PFC and dentate gyrus (DG) of hippocampus. Similarly, relative to Cur, SLCP produced a larger decrease of pyknotic, or tangle-like, neurons in PFC, CA1, and CA3 areas of hippocampus after 5 days of treatment. Both Cur and or SLCP significantly reduced GFAP-IR and Iba-1-IR in PFC, in the striatum as well as CA1, CA3, DG, subicular complex of hippocampus, and the entorhinal cortex in the 5xFAD mice after 5 days of treatment. CONCLUSIONS: The use of SLCP provides more anti-amyloid, anti-inflammatory, and neuroprotective outcomes than does Cur in the 5xFAD mouse model of AD.

Zika virus induces astrocyte differentiation in neural stem cells.

Zika virus (ZIKV) is a rapidly emerging flavivirus that has been associated with a number of congenital neurological manifestations. Here, we show that ZIKV replicated efficiently in mouse neural stem cells (mNSCs). ZIKV infection caused a cytopathic effect without affecting cell viability, yet led to a significant decrease in the number of proteins secreted into mNSC supernatants. A gene expression array of neural stem cell progenitor and differentiation markers suggested that infection reduced the number of neuronal and oligodendrocyte progenitors while increasing the number of astrocyte progenitors. Infection in astrocytes increased transcription of key genes involved in the antiviral response. These data provide molecular and cellular evidence that ZIKV significantly alters neural development in the vertebrate host and that astrocyte differentiation may be a protective response that limits neuropathogenesis.

Use of Polyamidoamine Dendrimers in Brain Diseases.

Polyamidoamine (PAMAM) dendrimers are one of the smallest and most precise nanomolecules available today, which have promising applications for the treatment of brain diseases. Each aspect of the dendrimer (core, size or generation, size of cavities, and surface functional groups) can be precisely modulated to yield a variety of nanocarriers for delivery of drugs and genes to brain cells in vitro or in vivo. Two of the most important criteria to consider when using PAMAM dendrimers for neuroscience applications is their safety profile and their potential to be prepared in a reproducible manner. Based on these criteria, features of PAMAM dendrimers are described to help the neuroscience researcher to judiciously choose the right type of dendrimer and the appropriate method for loading the drug to form a safe and effective delivery system to the brain.

Expanding Collaborations between the Neuroscience Training Committee of the Society for Neuroscience and the Faculty for Undergraduate Neuroscience.

At the FUN workshop at Dominican University in July 2017, we presented a session on activities of the Neuroscience Training Committee (NTC) of the Society for Neuroscience (SfN). We focused on activities that pertain to undergraduate neuroscience education and how NTC could help the Faculty for Undergraduate Neuroscience (FUN) achieve its goals and objectives in the coming years. We outlined a brief history of how FUN became involved with the Association of Neuroscience Departments and Programs, one of the parent organizations from which the current NTC evolved. We provided examples of the efforts that the NTC is making to include more activities that support undergraduate neuroscience education, including providing support for FUN workshops and its accompanying special issue in the Journal of Undergraduate Neuroscience Education (JUNE). In addition, we solicited feedback from the participants at this session for ideas for how the NTC could better serve members of FUN. This discussion yielded questions about the value of Institutional Program (IP) memberships for undergraduate institutions and suggestions, such as reduced membership fees and discounts for abstracts, and/or registration attendance at the annual SfN conference for individuals at colleges or universities with IP membership. Other suggestions included providing short courses in undergraduate pedagogy (including program and curriculum development), sponsorships for developing new assessment tools or innovative curricula, and providing more support for JUNE. We concluded our session by encouraging FUN members to become active in NTC programs and to seek membership to the NTC and other SfN committees to ensure that the voice of undergraduate neuroscience education will continue to be heard.

A comparative study of dietary curcumin, nanocurcumin, and other classical amyloid-binding dyes for labeling and imaging of amyloid plaques in brain tissue of 5×-familial Alzheimer's disease mice.

Deposition of amyloid beta protein (Aß) is a key component in the pathogenesis of Alzheimer's disease (AD). As an anti-amyloid natural polyphenol, curcumin (Cur) has been used as a therapy for AD. Its fluorescent activity, preferential binding to Aß, as well as structural similarities with other traditional amyloid-binding dyes, make it a promising candidate for labeling and imaging of Aß plaques in vivo. The present study was designed to test whether dietary Cur and nanocurcumin (NC) provide more sensitivity for labeling and imaging of Aß plaques in brain tissues from the 5×-familial AD (5×FAD) mice than the classical Aß-binding dyes, such as Congo red and Thioflavin-S. These comparisons were made in postmortem brain tissues from the 5×FAD mice. We observed that Cur and NC labeled Aß plaques to the same degree as Aß-specific antibody and to a greater extent than those of the classical amyloid-binding dyes. Cur and NC also labeled Aß plaques in 5×FAD brain tissues when injected intraperitoneally. Nanomolar concentrations of Cur or NC are sufficient for labeling and imaging of Aß plaques in 5×FAD brain tissue. Cur and NC also labeled different types of Aß plaques, including core, neuritic, diffuse, and burned-out, to a greater degree than other amyloid-binding dyes. Therefore, Cur and or NC can be used as an alternative to Aß-specific antibody for labeling and imaging of Aß plaques ex vivo and in vivo. It can provide an easy and inexpensive means of detecting Aß-plaque load in postmortem brain tissue of animal models of AD after anti-amyloid therapy.

Role of Epigenetics in Stem Cell Proliferation and Differentiation: Implications for Treating Neurodegenerative Diseases.

The main objectives of this review are to survey the current literature on the role of epigenetics in determining the fate of stem cells and to assess how this information can be used to enhance the treatment strategies for some neurodegenerative disorders, like Huntington's disease, Parkinson's disease and Alzheimer's disease. Some of these epigenetic mechanisms include DNA methylation and histone modifications, which have a direct impact on the way that genes are expressed in stem cells and how they drive these cells into a mature lineage. Understanding how the stem cells are behaving and giving rise to mature cells can be used to inform researchers on effective ways to design stem cell-based treatments. In this review article, the way in which the basic understanding of how manipulating this process can be utilized to treat certain neurological diseases will be presented. Different genetic factors and their epigenetic changes during reprogramming of stem cells into induced pluripotent stem cells (iPSCs) have significant potential for enhancing the efficacy of cell replacement therapies.

Transplants of adult mesenchymal and neural stem cells provide neuroprotection and behavioral sparing in a transgenic rat model of Huntington's disease.

Stem cells have gained significant interest as a potential treatment of neurodegenerative diseases, including Huntington's disease (HD). One source of these cells is adult neural stem cells (aNSCs), which differentiate easily into neuronal lineages. However, these cells are vulnerable to immune responses following transplantation. Another source is bone-marrow-derived mesenchymal stem cells (MSCs), which release neurotrophic factors and anti-inflammatory cytokines following transplantation, and are less vulnerable to rejection. The goal of this study was to compare the efficacy of transplants of MSCs, aNSCs, or cotransplants of MSCs and aNSCs for reducing deficits in a transgenic rat model of HD. HD rats received intrastriatal transplantations of 400,000 MSCs, aNSCs, or a combination of MSCs/aNSCs, while wild-type and HD controls were given vehicle. Rats were tested on the rotarod over the course of 20 weeks. The results indicated that transplants of: (a) aNSCs produced a strong immune response and conferred short-term behavioral benefits; (b) MSCs elicited a relatively weak immune response, and provided a longer term behavioral benefit; and (c) combined MSCs and aNSCs conferred long-term behavioral benefits and increased survival of the transplanted aNSCs. The finding that cotransplanting MSCs with aNSCs can prolong aNSC survival and provide greater behavioral sparing than when the transplants contains only aNSCs suggests that MSCs are capable of creating a more suitable microenvironment for aNSC survival. This cotransplantation strategy may be useful as a future therapeutic option for treating HD, especially if long-term survival of differentiated cells proves to be critically important for preserving lasting functional outcomes.

Best Practices: The Neuroscience Program at Central Michigan University.

The original design of our program at Central Michigan University (CMU) and its evolving curriculum were directly influenced by Faculty for Undergraduate (FUN) workshops at Davidson College, Oberlin College, Trinity College, and Macalester College. The course content, laboratory exercises, and pedagogy used were informed by excellent articles in the Journal of Undergraduate Neuroscience Education (JUNE) and presentations at these FUN workshops and meetings over the years. Like the program at Baldwin-Wallace College, which was a previous winner of the Undergraduate Neuroscience Program of the Year Award, as selected by the Committee on Neuroscience Departments and Programs (CNDP) of the Society for Neuroscience (SfN, our program stresses the importance of inquiry-based, hands-on research experience for our undergraduates and utilizes a peer-mentoring system. A distinct advantage that is employed at CMU is the use of graduate student mentors, which allows us to expand our peer-mentorship to distinct research teams that are focused on a specific research project. Developing our program was not easy. The present manuscript reviews the long and arduous journey (including ways in which we navigated some difficult internal political issues) we made to build a strong program. Hopefully, this description may prove helpful for other evolving programs, in terms of avoiding certain pitfalls and overcoming obstacles, as well as selecting practices that have proven to be successful at our institution.

Career Transitions for Faculty Members committed to Undergraduate Neuroscience Education.

This article highlights some of the critical issues that were discussed during a breakout session on career transitions at the 2014 Faculty for Undergraduate Neuroscience (FUN) Workshop at Ithaca College on Undergraduate Neuroscience Education: Challenges and Solutions in Creating and Sustaining Programs. Topics included: (1) transitioning from graduate school or a postdoc position to an assistant professor position; (2) preparing for promotion and tenure decisions; (3) balancing teaching, research, and service during a career in academics; (4) exploring alternative career options, including moving to another institution, taking on an administrative position, and working in industry; and (5) deciding when and how to retire. Much of the discussion focused on special challenges that women and minorities face in the academic environment. Participants offered valuable insights and suggestions for helping new faculty members prepare for reappointment, promotion, and tenure decisions, including utilizing networking connections within FUN for letters of support and collaborative opportunities. These networking opportunities were also valued by participants who were in rather unique positions, such as transitioning from a purely administrative role back to a regular faculty position or handling the extra burden of being a chair or program director with essentially the same research and grant-writing expectations of a regular faculty member. The session proved to be enlightening for most participants and though several questions and concerns remained unanswered, several ideas and insights were shared by the participants and a sense of empathy for the unique circumstances many of the participants were experiencing provided an atmosphere of comradery and support that often emanates from these FUN workshop sessions.

Use of genetically modified mesenchymal stem cells to treat neurodegenerative diseases.

The transplantation of mesenchymal stem cells (MSCs) for treating neurodegenerative disorders has received growing attention recently because these cells are readily available, easily expanded in culture, and when transplanted, survive for relatively long periods of time. Given that such transplants have been shown to be safe in a variety of applications, in addition to recent findings that MSCs have useful immunomodulatory and chemotactic properties, the use of these cells as vehicles for delivering or producing beneficial proteins for therapeutic purposes has been the focus of several labs. In our lab, the use of genetic modified MSCs to release neurotrophic factors for the treatment of neurodegenerative diseases is of particular interest. Specifically, glial cell-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain derived neurotrophic factor (BDNF) have been recognized as therapeutic trophic factors for Parkinson's, Alzheimer's and Huntington's diseases, respectively. The aim of this literature review is to provide insights into: (1) the inherent properties of MSCs as a platform for neurotrophic factor delivery; (2) the molecular tools available for genetic manipulation of MSCs; (3) the rationale for utilizing various neurotrophic factors for particular neurodegenerative diseases; and (4) the clinical challenges of utilizing genetically modified MSCs.

Using microdialysis to monitor dopaminergic support of limb-use control following mesencephalic neurosphere transplantation in a rodent model of Parkinson's Disease.

Controlled nigrostriatal dopamine release supports effective limb use during locomotion coordination that becomes compromised after this pathway deteriorates in Parkinson's Disease (PD). How dopamine release relates to active ongoing behavior control remains unknown. Restoring proper release strategy appears important to successful PD treatment with transplanted dopamine-producing stem cells. This is suggested by apparently distinct behavioral support from tonic or phasic release and corresponding requirements of requisite afferent control exhibited by intact nigrostriatal neurons. Our laboratory previously demonstrated that transplanted dopaminergic cells can elicit skilled movement recovery known to depend on phasic dopamine release. However, efforts to measure this movement-related dopamine release yielded seemingly paradoxical, incongruent results. In response, here we explored whether those previous observations derived from rapid reuptake transport into either transplanted cells or residual, lesion-surviving terminals. We confirmed this using minimal reuptake blockade during intrastriatal microdialysis. After unilateral dopamine depletion, rats received transplants and were subjected to our swimming protocol. Among dopamine-depleted and transplanted rats, treatment supported restoration of limb movement symmetry. Interestingly, subsequent reuptake-restricted microdialysis confirmed distinct swimming-induced dopamine increases clearly occurred among these lesioned/transplanted subjects. Thus, phasic firing control appears to contribute to transplant-derived recovery in Parkinsonian animals.

Correction: Bowers et al. Tart Cherry Extract and Omega Fatty Acids Reduce Behavioral Deficits and Gliosis in the 5xFAD Mouse Model of Alzheimer's Disease. Brain Sci. 2021, 11, 1423.

There is an error in the title of the published paper [...].

Shared innovations in education: writing and reviewing for the undergraduate neuroscience community.

In the Fall of 2002, the Faculty for Undergraduate Neuroscience (FUN) began publication of its flagship journal, the Journal of Undergraduate Neuroscience Education (JUNE). For the past ten years, JUNE has been a major forum for the free exchange of information among undergraduate neuroscience educators. Numerous articles on laboratory exercises, media, pedagogy, curriculum, and issues pertinent to neuroscience educators have been published in JUNE during the past decade. Given the vast expertise in pedagogy amongst the FUN membership and within the undergraduate neuroscience education community at large, we strongly encourage all FUN members and JUNE readers to become actively involved in JUNE by contributing manuscripts and/or by offering your services as a reviewer.