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 [...].

Tart Cherry Extract and Omega Fatty Acids Reduce Behavioral Deficits, Gliosis, and Amyloid-Beta Deposition in the 5xFAD Mouse Model of Alzheimer's Disease.

Combined treatments using polyphenols and omega fatty acids provide several therapeutic benefits for a variety of age-related disorders, including Alzheimer's disease (AD). Previously, we found a commercial product, Total Body Rhythm (TBR), consisting of tart cherry extract, a potent polyphenol, and omega fatty acids, significantly reduced memory, and neuropathological deficits in the 192 IgG-saporin mouse model of AD. The present study assessed the efficacy of TBR for treating behavioral and neuropathological deficits in the 5xFAD model of AD. Both 6- and 12-month-old 5xFAD mice and age-matched wild-type controls received TBR (60 mg/kg) or the equivalent dose of vehicle (0.5% methylcellulose) via oral administration, every other day for two months. All mice were tested in the open field (OF), novel object recognition (NOR), and the Morris water maze (MWM) tasks. In addition, neuronal morphology, neurodegeneration, Aß plaque load, and glial activation were assessed. TBR treatment reduced memory deficits in the MWM and NOR tests and lessened anxiety levels in the OF task, mostly in the 6-month-old male mice. TBR also protected against neuron loss, reduced activation of astrocytes and microglia, primarily in 6-month-old mice, and attenuated Aß deposition. These results suggest that the combination of tart cherry extract and omega fatty acids in TBR can reduce AD-like deficits in 5xFAD mice.

Tetrahydrocurcumin Has Similar Anti-Amyloid Properties as Curcumin: In Vitro Comparative Structure-Activity Studies.

Despite its potent anti-amyloid properties, the utility of curcumin (Cur) for the treatment of Alzheimer's disease (AD) is limited due to its low bioavailability. Tetrahydrocurcumin (THC), a more stable metabolite has been found in Cur-treated tissues. We compared the anti-amyloid and neuroprotective properties of curcumin, bisdemethoxycurcumin (BDMC), demethoxycurcumin (DMC) and THC using molecular docking/dynamics, in-silico and in vitro studies. We measured the binding affinity, H-bonding capabilities of these compounds with amyloid beta protein (Aß). Dot blot assays, photo-induced cross linking of unmodified protein (PICUP) and transmission electron microscopy (TEM) were performed to monitor the Aß aggregation inhibition using these compounds. Neuroprotective effects of these derivatives were evaluated in N2a, CHO and SH-SY5Y cells using Aß42 (10 µM) as a toxin. Finally, Aß-binding capabilities were compared in the brain tissue derived from the 5× FAD mouse model of AD. We observed that THC had similar binding capability and Aß aggregation inhibition such as keto/enol Cur and it was greater than BDMC and DMC. All these derivatives showed a similar degree of neuroprotection in vitro and labeled Aß-plaques ex vivo. Overall, ECur and THC showed greater anti-amyloid properties than other derivatives. Therefore, THC, a more stable and bioavailable metabolite may provide greater therapeutic efficacy in AD than other turmeric derivatives.

Curcugreen Treatment Prevented Splenomegaly and Other Peripheral Organ Abnormalities in 3xTg and 5xFAD Mouse Models of Alzheimer's Disease.

Metabolic dysfunction and immune disorders are common in Alzheimer's disease (AD). The mechanistic details of these epiphenomena in AD are unclear. Here, we have investigated whether a highly bioavailable curcuminoid formulation, curcugreen (CGR), can prevent abnormalities in peripheral organs of two mouse models of AD. Eighteen- and 24-month-old male and female 3xTg and 5xFAD mice were treated with CGR (100 mg/kg) for 2 months, orally. Cytoarchitectural changes of spleen, liver, kidney and lungs were studied by H&E stain. Apoptotic death was confirmed by TUNEL staining. Amyloid deposition, pTau levels, proinflammatory, anti-inflammatory and cell death/survival markers were studied by Western blots. Curcugreen reduced the observed splenomegaly (3xTg) and degeneration of spleen, granulomatous inflammation in the kidney, hepatic sinusoidal disorganization, hepatocellular hypertrophy, inflammation of the central hepatic vein, infiltration and swelling of lung tissues, and apoptotic death in all these areas in both 3xTg and 5xFAD mice. Similarly, CGR decreased amyloid deposition, pTau, proinflammatory markers, cell loss and decrements in anti-inflammatory markers in both 3xTg and 5xFAD mice. Peripheral organ abnormalities and inflammatory responses in AD were ameliorated by curcuminoid treatment.

Preservation of dendritic spine morphology and postsynaptic signaling markers after treatment with solid lipid curcumin particles in the 5xFAD mouse model of Alzheimer's amyloidosis.

BACKGROUND: Synaptic failure is one of the principal events associated with cognitive dysfunction in Alzheimer's disease (AD). Preservation of existing synapses and prevention of synaptic loss are promising strategies to preserve cognitive function in AD patients. As a potent natural anti-oxidant, anti-amyloid, and anti-inflammatory polyphenol, curcumin (Cur) shows great promise as a therapy for AD. However, hydrophobicity of natural Cur limits its solubility, stability, bioavailability, and clinical utility for AD therapy. We have demonstrated that solid lipid curcumin particles (SLCP) have greater therapeutic potential than natural Cur in vitro and in vivo models of AD. In the present study, we have investigated whether SLCP has any preservative role on affected dendritic spines and synaptic markers in 5xFAD mice. METHODS: Six- and 12-month-old 5xFAD and age-matched wild-type mice received oral administration of SLCP (100 mg/kg body weight) or equivalent amounts of vehicle for 2 months. Neuronal morphology, neurodegeneration, and amyloid plaque load were investigated from prefrontal cortex (PFC), entorhinal cortex (EC), CA1, CA3, and the subicular complex (SC). In addition, the dendritic spine density from apical and basal branches was studied by Golgi-Cox stain. Further, synaptic markers, such as synaptophysin, PSD95, Shank, Homer, Drebrin, Kalirin-7, CREB, and phosphorylated CREB (pCREB) were studied using Western blots. Finally, cognitive and motor functions were assessed using open-field, novel object recognition (NOR) and Morris water maze (MWM) tasks after treatment with SLCP. RESULTS: We observed an increased number of pyknotic and degenerated cells in all these brain areas in 5xFAD mice and SLCP treatment partially protected against those losses. Decrease in dendritic arborization and dendritic spine density from primary, secondary, and tertiary apical and basal branches were observed in PFC, EC, CA1, and CA3 in both 6- and 12-month-old 5xFAD mice, and SLCP treatments partially preserved the normal morphology of these dendritic spines. In addition, pre- and postsynaptic protein markers were also restored by SLCP treatment. Furthermore, SLCP treatment improved NOR and cognitive function in 5xFAD mice. CONCLUSIONS: Overall, these findings indicate that use of SLCP exerts neuroprotective properties by decreasing amyloid plaque burden, preventing neuronal death, and preserving dendritic spine density and synaptic markers in the 5xFAD mice.

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.

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.

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.

Combination treatment of berberine and solid lipid curcumin particles increased cell death and inhibited PI3K/Akt/mTOR pathway of human cultured glioblastoma cells more effectively than did individual treatments.

The treatment of glioblastoma is challenging for the clinician, due to its chemotherapeutic resistance. Recent findings suggest that targeting glioblastoma using anti-cancer natural polyphenols is a promising strategy. In this context, curcumin and berberine have been shown to have potent anti-cancer and anti-inflammatory effects against several malignancies. Due to the poor solubility and limited bioavailability, these compounds have limited efficacy for treating cancer. However, use of a formulation of curcumin with higher bioavailability or combining it with berberine as a co-treatment may be proving to be more efficacious against cancer. Recently, we demonstrated that solid lipid curcumin particles (SLCPs) provided more bioavailability and anti-cancer effects in cultured glioblastoma cells than did natural curcumin. Interestingly, a combination of curcumin and berberine has proven to be more effective in inhibiting growth and proliferation of cancer in the liver, breast, lung, bone and blood. However, the effect of combining these drugs for treating glioblastoma, especially with respect to its effect on activating the PI3K/Akt/mTOR pathways has not been studied. Therefore, we decided to assess the co-treatment effects of these drugs on two different glioblastoma cell lines (U-87MG and U-251MG) and neuroblastoma cell lines (SH-SY5Y) derived from human tissue. In this study, we compared single and combination (1:5) treatment of SLCP (20 µM) and berberine (100 µM) on measures of cell viability, cell death markers, levels of c-Myc and p53, along with biomarkers of the PI3K/Akt/mTOR pathways after 24-48 h of incubation. We found that co-treatment of SLCP and berberine produced more glioblastoma cell death, more DNA fragmentation, and significantly decreased ATP levels and reduced mitochondrial membrane potential than did single treatments in both glioblastoma cells lines. In addition, we observed that co-treatment inhibited the PI3K/Akt/mTOR pathway more efficiently than their single treatments. Our study suggests that combination treatments of SLCP and berberine may be a promising strategy to reduce or prevent glioblastoma growth in comparison to individual treatments using either compound.

Labeling and Imaging of Amyloid Plaques in Brain Tissue Using the Natural Polyphenol Curcumin.

Deposition of amyloid beta protein (Aß) in extra- and intracellular spaces is one of the hallmark pathologies of Alzheimer's disease (AD). Therefore, detection of the presence of Aß in AD brain tissue is a valuable tool for developing new treatments to prevent the progression of AD. Several classical amyloid binding dyes, fluorochrome, imaging probes, and Aß-specific antibodies have been used to detect Aß histochemically in AD brain tissue. Use of these compounds for Aß detection is costly and time consuming. However, because of its intense fluorescent activity, high-affinity, and specificity for Aß, as well as structural similarities with traditional amyloid binding dyes, curcumin (Cur) is a promising candidate for labeling and imaging of Aß plaques in postmortem brain tissue. It is a natural polyphenol from the herb Curcuma longa. In the present study, Cur was used to histochemically label Aß plaques from both a genetic mouse model of 5x familial Alzheimer's disease (5xFAD) and from human AD tissue within a minute. The labeling capability of Cur was compared to conventional amyloid binding dyes, such as thioflavin-S (Thio-S), Congo red (CR), and Fluoro-jade C (FJC), as well as Aß-specific antibodies (6E10 and A11). We observed that Cur is the most inexpensive and quickest way to label and image Aß plaques when compared to these conventional dyes and is comparable to Aß-specific antibodies. In addition, Cur binds with most Aß species, such as oligomers and fibrils. Therefore, Cur could be used as the most cost-effective, simple, and quick fluorochrome detection agent for Aß plaques.

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.

Silencing of the Mutant Huntingtin Gene through CRISPR-Cas9 Improves the Mitochondrial Biomarkers in an In Vitro Model of Huntington's Disease.

During the 25-year history of the American Society for Neural Therapy and Repair (ASNTR) there have been several breakthroughs in the area of neurotherapeutics, which was the case during the 2014-2105 year when one of us (GLD) had the privilege of serving as its president. During that year, the use of a newly developed gene-editing tool, the CRISPR-Cas9 system, started to skyrocket. Although scientists unraveled the use of "clustered regularly interspaced short palindromic repeats" (CRISPR) and its associated genes from the Cas family as an evolved mechanism of some bacterial and archaeal genomes to protect themselves from being hijacked by invasive viral genes, its use as a therapeutic tool was not fully appreciated until further research revealed how this system operated and how it might be developed technologically to manipulate genes of any species. By 2015, this technology had exploded to the point that close to 2,000 papers that used this technology were published during that year alone.