Antioxidant Blend of Curcumin and Broccoli Seed Extract Exhibits Protective Effect on Neurodegeneration and Promotes Drosophila Lifespan.

Antioxidants and related compounds are anti-inflammatory and exhibit great potential in promoting human health. They are also often considered to be important elements in the process of neurodegeneration. Here we describe a antioxidant blend of Curcumin and Broccoli Seed Extract (BSE). Flies treated with the blend exhibit extended lifespan. RNA-seq analysis of samples from adult fly brains reveals a wide array of new genes with differential expression upon treatment with the blend. Interestingly, abolishing expression of some of the identified genes in dopaminergic (DA) neurons does not affect DA neuron number. Taken together, our findings reveal an antioxidant blend that promotes fly longevity and exhibits protective effect over neurodegeneration, demonstrating the importance of antioxidants in health and pathology.

Neuroprotective Effects of Ginsenoside Rg1 against Hyperphosphorylated Tau-Induced Diabetic Retinal Neurodegeneration via Activation of IRS-1/Akt/GSK3ß Signaling.

We have recently demonstrated that tau hyperphosphorylation causes diabetic synaptic neurodegeneration of retinal ganglion cells (RGCs), which might be the earliest affair during the pathogenesis of diabetic retinopathy (DR). Thus, there is a pressing need to seek therapeutic agents possessing neuroprotective effects against tau hyperphosphorylation in RGCs for arresting the progression of DR. Here, using a well-characterized diabetes model of db/db mouse, we discovered that topical ocular application of 10 mg/kg/day of ginsenoside Rg1 (GRg1), one of the major active ingredients extracted from Panax ginseng and Panax notoginseng, ameliorated hyperphosphorylated tau-triggered RGCs synaptic neurodegeneration in diabetic mice. The neuroprotective effects of GRg1 on diabetic retinae were abrogated when retinal IRS-1 or Akt was suppressed by intravitreal injection with si-IRS-1 or topically coadministered with a specific inhibitor of Akt, respectively. However, selective repression of retinal GSK3ß by intravitreal administration of si-GSK3ß rescued the neuroprotective properties of GRg1 when Akt was inactivated. Therefore, the present study showed for the first time that GRg1 can prevent hyperphosphorylated tau-induced synaptic neurodegeneration of RGCs via activation of IRS-1/Akt/GSK3ß signaling in the early phase of DR. Moreover, our data clarify the potential therapeutic significance of GRg1 for neuroprotective intervention strategies of DR.

Molecular layer interneurons shape the spike activity of cerebellar Purkinje cells.

Purkinje cells receive synaptic input from several classes of interneurons. Here, we address the roles of inhibitory molecular layer interneurons in establishing Purkinje cell function in vivo. Using conditional genetics approaches in mice, we compare how the lack of stellate cell versus basket cell GABAergic neurotransmission sculpts the firing properties of Purkinje cells. We take advantage of an inducible Ascl1CreER allele to spatially and temporally target the deletion of the vesicular GABA transporter, Vgat, in developing neurons. Selective depletion of basket cell GABAergic neurotransmission increases the frequency of Purkinje cell simple spike firing and decreases the frequency of complex spike firing in adult behaving mice. In contrast, lack of stellate cell communication increases the regularity of Purkinje cell simple spike firing while increasing the frequency of complex spike firing. Our data uncover complementary roles for molecular layer interneurons in shaping the rate and pattern of Purkinje cell activity in vivo.

Vulnerability of frontal brain neurons for the toxicity of expanded ataxin-3.

Spinocerebellar ataxia type 3 (SCA3) is caused by the expansion of CAG repeats in the ATXN3 gene leading to an elongated polyglutamine tract in the ataxin-3 protein. Previously, we demonstrated that symptoms of SCA3 are reversible in the first conditional mouse model for SCA3 directing ataxin-3 predominantly to the hindbrain. Here, we report on the effects of transgenic ataxin-3 expression in forebrain regions. Employing the Tet-off CamKII-promoter mouse line and our previously published SCA3 responder line, we generated double transgenic mice (CamKII/MJD77), which develop a neurological phenotype characterized by impairment in rotarod performance, and deficits in learning new motor tasks as well as hyperactivity. Ataxin-3 and ubiquitin-positive inclusions are detected in brains of double transgenic CamKII/MJD77 mice. After turning off the expression of pathologically expanded ataxin-3, these inclusions disappear. However, the observed phenotype could not be reversed, very likely due to pronounced apoptotic cell death in the frontal brain. Our data demonstrate that cerebellar expression is not required to induce a neurological phenotype using expanded ATXN3 as well as the pronounced sensibility of forebrain neurons for toxic ataxin-3.

Impaired Mitochondrial Fatty Acid Synthesis Leads to Neurodegeneration in Mice.

There has been a growing interest toward mitochondrial fatty acid synthesis (mtFAS) since the recent discovery of a neurodegenerative human disorder termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration), which is caused by mutations in the mitochondrial enoyl-CoA/ACP (acyl carrier protein) reductase (MECR) carrying out the last step of mtFAS. We show here that MECR protein is highly expressed in mouse Purkinje cells (PCs). To elucidate mtFAS function in neural tissue, here, we generated a mouse line with a PC-specific knock-out (KO) of Mecr, leading to inactivation of mtFAS confined to this cell type. Both sexes were studied. The mitochondria in KO PCs displayed abnormal morphology, loss of protein lipoylation, and reduced respiratory chain enzymatic activities by the time these mice were 6 months of age, followed by nearly complete loss of PCs by 9 months of age. These animals exhibited balancing difficulties ∼7 months of age and ataxic symptoms were evident from 8-9 months of age on. Our data show that impairment of mtFAS results in functional and ultrastructural changes in mitochondria followed by death of PCs, mimicking aspects of the clinical phenotype. This KO mouse represents a new model for impaired mitochondrial lipid metabolism and cerebellar ataxia with a distinct and well trackable cellular phenotype. This mouse model will allow the future investigation of the feasibility of metabolite supplementation approaches toward the prevention of neurodegeneration due to dysfunctional mtFAS.SIGNIFICANCE STATEMENT We have recently reported a novel neurodegenerative disorder in humans termed MEPAN (mitochondrial enoyl reductase protein associated neurodegeneration) (Heimer et al., 2016). The cause of neuron degeneration in MEPAN patients is the dysfunction of the highly conserved mitochondrial fatty acid synthesis (mtFAS) pathway due to mutations in MECR, encoding mitochondrial 2-enoyl-CoA/ACP reductase. The report presented here describes the analysis of the first mouse model suffering from mtFAS-defect-induced neurodegenerative changes due to specific disruption of the Mecr gene in Purkinje cells. Our work sheds a light on the mechanisms of neurodegeneration caused by mtFAS deficiency and provides a test bed for future treatment approaches.

MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways.

MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here, we describe a neuroprotective function of miR-132, the miRNA most significantly downregulated in neurons in Alzheimer's disease. We demonstrate that miR-132 protects primary mouse and human wild-type neurons and more vulnerable Tau-mutant neurons against amyloid ß-peptide (Aß) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF-Tau pathology and neurodegeneration, and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3ß, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.

Modeling Parkinson's Disease in C. elegans.

Parkinson's disease (PD) is an adult onset neurodegenerative disease that is characterized by selective degeneration of neurons primarily in the substantia nigra. At present, the pathogenesis of PD is incompletely understood and there are no neuroprotective treatments available. Accurate animal models of PD provide the opportunity to elucidate disease mechanisms and identify therapeutic targets. This review focuses on C. elegans models of PD, including both genetic and toxicant models. This microscopic worm offers several advantages for the study of PD including ease of genetic manipulation, ability to complete experiments rapidly, low cost, and ability to perform large scale screens for disease modifiers. A number of C. elegans models of PD have been generated including transgenic worms that express α-synuclein or LRRK2, and worms with deletions in PRKN/pdr-1, PINK1/pink-1, DJ-1/djr-1.1/djr-1.2 and ATP13A2/catp-6. These worms have been shown to exhibit multiple phenotypic deficits including the loss of dopamine neurons, disruption of dopamine-dependent behaviors, increased sensitivity to stress, age-dependent aggregation, and deficits in movement. As a result, these phenotypes can be used as outcome measures to gain insight into disease pathogenesis and to identify disease modifiers. In this way, C. elegans can be used as an experimental tool to elucidate mechanisms involved in PD and to find novel therapeutic targets that can subsequently be validated in other models.

A pharmacological screen for compounds that rescue the developmental lethality of a Drosophila ATM mutant.

Ataxia-telangiectasia (A-T) is a neurodegenerative disease caused by mutation of the A-T mutated (ATM) gene. ATM encodes a protein kinase that is activated by DNA damage and phosphorylates many proteins, including those involved in DNA repair, cell cycle control, and apoptosis. Characteristic biological and molecular functions of ATM observed in mammals are conserved in Drosophila melanogaster. As an example, conditional loss-of-function ATM alleles in flies cause progressive neurodegeneration through activation of the innate immune response. However, unlike in mammals, null alleles of ATM in flies cause lethality during development. With the goals of understanding biological and molecular roles of ATM in a whole animal and identifying candidate therapeutics for A-T, we performed a screen of 2400 compounds, including FDA-approved drugs, natural products, and bioactive compounds, for modifiers of the developmental lethality caused by a temperature-sensitive ATM allele (ATM8) that has reduced kinase activity at non-permissive temperatures. Ten compounds reproducibly suppressed the developmental lethality of ATM8 flies, including Ronnel, which is an organophosphate. Ronnel and other suppressor compounds are known to cause mitochondrial dysfunction or to inhibit the enzyme acetylcholinesterase, which controls the levels of the neurotransmitter acetylcholine, suggesting that detrimental consequences of reduced ATM kinase activity can be rescued by inhibiting the function of mitochondria or increasing acetylcholine levels. We carried out further studies of Ronnel because, unlike the other compounds that suppressed the developmental lethality of homozygous ATM8 flies, Ronnel was toxic to the development of heterozygous ATM8 flies. Ronnel did not affect the innate immune response of ATM8 flies, and it further increased the already high levels of DNA damage in brains of ATM8 flies, but its effects were not harmful to the lifespan of rescued ATM8 flies. These results provide new leads for understanding the biological and molecular roles of ATM and for the treatment of A-T.

The implication of neuronimmunoendocrine (NIE) modulatory network in the pathophysiologic process of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder implicitly marked by the substantia nigra dopaminergic neuron degeneration and explicitly characterized by the motor and non-motor symptom complexes. Apart from the nigrostriatal dopamine depletion, the immune and endocrine study findings are also frequently reported, which, in fact, have helped to broaden the symptom spectrum and better explain the pathogenesis and progression of PD. Nevertheless, based on the neural, immune, and endocrine findings presented above, it is still difficult to fully recapitulate the pathophysiologic process of PD. Therefore, here, in this review, we have proposed the neuroimmunoendocrine (NIE) modulatory network in PD, aiming to achieve a more comprehensive interpretation of the pathogenesis and progression of this disease. As a matter of fact, in addition to the classical motor symptoms, NIE modulatory network can also underlie the non-motor symptoms such as gastrointestinal, neuropsychiatric, circadian rhythm, and sleep disorders in PD. Moreover, the dopamine (DA)-melatonin imbalance in the retino-diencephalic/mesencephalic-pineal axis also provides an alternative explanation for the motor complications in the process of DA replacement therapy. In conclusion, the NIE network can be expected to deepen our understanding and facilitate the multi-dimensional management and therapy of PD in future clinical practice.

Granulovacuolar degeneration and unfolded protein response in mouse models of tauopathy and Aß amyloidosis.

Histopathological studies on the brains of tauopathy cases including cases with Alzheimer's disease (AD) demonstrate that neurons with hyperphosphorylated protein tau display granulovacuolar degeneration (GVD), as evidenced by vacuolar lesions harboring a central granule, together with markers of the activated unfolded protein response (UPR). In order to examine whether this hallmark is reproduced in animal models we studied the presence of GVD and the activated UPR in two complementary mouse models, pR5 mice with a tau pathology and APPSLxPS1mut mice with an amyloid plaque pathology. Neither GVD nor a significant activation of the UPR was found in both APPSLxPS1mut mice and in those regions in the pR5 brain where only neurons with an early stage of tau hyperphosphorylation were present. In contrast, those neurons that displayed a tau phospho-epitope signature that only appeared in old pR5 mice and also correlated with Gallyas-positive tangle staining harbored granulovacuolar lesions that were labeled with the GVD markers casein kinases 1δ and 1ε. Granulovacuolar lesions in pR5 mice were also labeled with the UPR markers phosphorylated PKR-like endoplasmic reticulum kinase, phosphorylated inositol-requiring enzyme 1α and phosphorylated eukaryotic initiation factor 2α. However, GVD was rarely observed in neurons bearing mature neurofibrillary tangles as evidenced by Congo red staining. Our results suggest that NFT-formation activates the UPR in pR5 mice and that it is the early stages of neurofibrillary tangle formation that are accompanied by GVD, in line with observations from studies on human autopsy cases.

Auditory analysis of xeroderma pigmentosum 1971-2012: hearing function, sun sensitivity and DNA repair predict neurological degeneration.

To assess the role of DNA repair in maintenance of hearing function and neurological integrity, we examined hearing status, neurological function, DNA repair complementation group and history of acute burning on minimal sun exposure in all patients with xeroderma pigmentosum, who had at least one complete audiogram, examined at the National Institutes of Health from 1971 to 2012. Seventy-nine patients, aged 1-61 years, were diagnosed with xeroderma pigmentosum (n = 77) or xeroderma pigmentosum/Cockayne syndrome (n = 2). A total of 178 audiograms were included. Clinically significant hearing loss (>20 dB) was present in 23 (29%) of 79 patients. Of the 17 patients with xeroderma pigmentosum-type neurological degeneration, 13 (76%) developed hearing loss, and all 17 were in complementation groups xeroderma pigmentosum type A or type D and reported acute burning on minimal sun exposure. Acute burning on minimal sun exposure without xeroderma pigmentosum-type neurological degeneration was present in 18% of the patients (10/55). Temporal bone histology in a patient with severe xeroderma pigmentosum-type neurological degeneration revealed marked atrophy of the cochlear sensory epithelium and neurons. The 19-year mean age of detection of clinically significant hearing loss in the patients with xeroderma pigmentosum with xeroderma pigmentosum-type neurological degeneration was 54 years younger than that predicted by international norms. The four frequency (0.5/1/2/4 kHz) pure-tone average correlated with degree of neurodegeneration (P < 0.001). In patients with xeroderma pigmentosum, aged 4-30 years, a four-frequency pure-tone average ≥10 dB hearing loss was associated with a 39-fold increased risk (P = 0.002) of having xeroderma pigmentosum-type neurological degeneration. Severity of hearing loss parallels neurological decline in patients with xeroderma pigmentosum-type neurological degeneration. Audiometric findings, complementation group, acute burning on minimal sun exposure and age were important predictors of xeroderma pigmentosum-type neurological degeneration. These results provide evidence that DNA repair is critical in maintaining neurological integrity of the auditory system.

Reactive astrocytes secrete lcn2 to promote neuron death.

Glial reaction is a common feature of neurodegenerative diseases. Recent studies have suggested that reactive astrocytes gain neurotoxic properties, but exactly how reactive astrocytes contribute to neurotoxicity remains to be determined. Here, we identify lipocalin 2 (lcn2) as an inducible factor that is secreted by reactive astrocytes and that is selectively toxic to neurons. We show that lcn2 is induced in reactive astrocytes in transgenic rats with neuronal expression of mutant human TAR DNA-binding protein 43 (TDP-43) or RNA-binding protein fused in sarcoma (FUS). Therefore, lcn2 is induced in activated astrocytes in response to neurodegeneration, but its induction is independent of TDP-43 or FUS expression in astrocytes. We found that synthetic lcn2 is cytotoxic to primary neurons in a dose-dependent manner, but is innocuous to astrocytes, microglia, and oligodendrocytes. Lcn2 toxicity is increased in neurons that express a disease gene, such as mutant FUS or TDP-43. Conditioned medium from rat brain slice cultures with neuronal expression of mutant TDP-43 contains abundant lcn2 and is toxic to primary neurons as well as neurons in cultured brain slice from WT rats. Partial depletion of lcn2 by immunoprecipitation reduced conditioned medium-mediated neurotoxicity. Our data indicate that reactive astrocytes secrete lcn2, which is a potent neurotoxic mediator.

Dopamine D2 receptor antagonism suppresses tau aggregation and neurotoxicity.

BACKGROUND: Tauopathies, including Alzheimer's disease and frontotemporal dementia, are diseases characterized by the formation of pathological tau protein aggregates in the brain and progressive neurodegeneration. Presently no effective disease-modifying treatments exist for tauopathies. METHODS: To identify drugs targeting tau neurotoxicity, we have used a Caenorhabditis elegans model of tauopathy to screen a drug library containing 1120 compounds approved for human use for the ability to suppress tau-induced behavioral effects. RESULTS: One compound, the typical antipsychotic azaperone, improved the motility of tau transgenic worms, reduced levels of insoluble tau, and was protective against neurodegeneration. We found that azaperone reduces insoluble tau in a human cell culture model of tau aggregation and that other antipsychotic drugs (flupenthixol, perphenazine, and zotepine) also ameliorate the effects of tau expression in both models. CONCLUSIONS: Reduction of dopamine signaling through the dopamine D2 receptor with the use of gene knockouts in Caenorhabditis elegans or RNA interference knockdown in human cell culture has similar protective effects against tau toxicity. These results suggest dopamine D2 receptor antagonism holds promise as a potential neuroprotective strategy for targeting tau aggregation and neurotoxicity.

Protection of retinal ganglion cells and retinal vasculature by Lycium barbarum polysaccharides in a mouse model of acute ocular hypertension.

Acute ocular hypertension (AOH) is a condition found in acute glaucoma. The purpose of this study is to investigate the protective effect of Lycium barbarum polysaccharides (LBP) and its protective mechanisms in the AOH insult. LBP has been shown to exhibit neuroprotective effect in the chronic ocular hypertension (COH) experiments. AOH mouse model was induced in unilateral eye for one hour by introducing 90 mmHg ocular pressure. The animal was fed with LBP solution (1 mg/kg) or vehicle daily from 7 days before the AOH insult till sacrifice at either day 4 or day 7 post insult. The neuroprotective effects of LBP on retinal ganglion cells (RGCs) and blood-retinal-barrier (BRB) were evaluated. In control AOH retina, loss of RGCs, thinning of IRL thickness, increased IgG leakage, broken tight junctions, and decreased density of retinal blood vessels were observed. However, in LBP-treated AOH retina, there was less loss of RGCs with thinning of IRL thickness, IgG leakage, more continued structure of tight junctions associated with higher level of occludin protein and the recovery of the blood vessel density when compared with vehicle-treated AOH retina. Moreover, we found that LBP provides neuroprotection by down-regulating RAGE, ET-1, Aß and AGE in the retina, as well as their related signaling pathways, which was related to inhibiting vascular damages and the neuronal degeneration in AOH insults. The present study suggests that LBP could prevent damage to RGCs from AOH-induced ischemic injury; furthermore, through its effects on blood vessel protection, LBP would also be a potential treatment for vascular-related retinopathy.

Chemical screen reveals small molecules suppressing fragile X premutation rCGG repeat-mediated neurodegeneration in Drosophila.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a progressive neurodegenerative disorder recognized in fragile X premutation carriers. Using Drosophila, we previously identified elongated non-coding CGG repeats in FMR1 allele as the pathogenic cause of FXTAS. Here, we use this same FXTAS Drosophila model to conduct a chemical screen that reveals small molecules that can ameliorate the toxic effects of fragile X premutation ribo-CGG (rCGG) repeats, among them several known phospholipase A(2) (PLA(2)) inhibitors. We show that specific inhibition of PLA(2) activity could mitigate the neuronal deficits caused by fragile X premutation rCGG repeats, including lethality and locomotion deficits. Furthermore, through a genetic screen, we identified a PLA(2) Drosophila ortholog that specifically modulates rCGG repeat-mediated neuronal toxicity. Our results demonstrate the utility of Drosophila models for unbiased small molecule screens and point to PLA(2) as a possible therapeutic target to treat FXTAS.

Decreased expression of myelin gene regulatory factor in Niemann-Pick type C 1 mouse.

Niemann-Pick type C 1 (NPC1) disease is an autosomal recessive cholesterol transport defect resulting in a neurodegenerative process in patients mainly at an early age, although some patients may start with manifestation in adult. Since loss of myelin is considered as a main pathogenetic factor, the precise mechanism inducing dysmylination in NPC1 disease is still unclear. In the present study, a quantitative evaluation on the myelin protein and its regulatory factors of oligodendrocytes, such as SRY-related HMG-box 10 (Sox10), Yin Yang 1 factor (YY1) and myelin gene regulatory factor (MRF), in different parts of the brain and spinal cord was performed in NPC1-mutant mice. The results showed that NPC1 protein was expressed in oligodendrocytes and the amount of myelin protein was generally decreased in all parts of the brain and spinal cord in NPC1-mutant mice. Compared to wild type, the amount of Sox10 and YY1 was not different in NPC1-mutant mice, but MRF was significantly decreased, suggesting a possible mechanism perturbing differentiation of oligodendrocytes and the myelination process in the NPC1-mutant mouse.

Enhanced neurodegeneration after a high dose of methamphetamine in adenosine A3 receptor null mutant mice.

Previous reports have indicated that adenosine A3 receptor (A3R) knockout mice are more sensitive to ischemic or hypoxic brain injury. The purpose of this study was to examine if suppression of A3R expression is associated with increase in sensitivity to injury induced by a high dose of methamphetamine (Meth). Adult male A3R null mutant (-/-) mice and their controls (+/+) were injected with four doses (2 h apart) of Meth (10 mg/kg) or saline. Animals were placed in a behavioral activity chamber, equipped with food and water, for 52 h starting from one day after injections. The first 4 h were used for studying exploratory behaviors, and the next 48 h were used to measure locomotor activity. High doses of Meth equally reduced the 4-h exploratory behavior in -/- and +/+ mice. Meth suppressed locomotor activity between 4 and 52 h in both groups, with a greater reduction being found in the -/- mice. Brain tissues were collected at 3 days after the Meth or saline injections. Meth treatment reduced striatal dopamine (DA) levels in both +/+ and -/- mice with an increase in 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio being found only in -/- animals. Meth also significantly increased ionized calcium-binding adaptor molecule 1 (Iba-1) and cleaved caspase-3 level in striatum, as well as Iba-1 and TNFα mRNA expression in nigra in -/-, compared to +/+, mice. Previous studies have shown that pharmacological suppression of vesicular monoamine transport 2 (VMAT2) by reserpine enhanced Meth toxicity by increasing cytosolic DA and inflammation. A significant reduction in striatal VMAT2 expression was found in -/- mice compared to +/+ mice, suggesting that increase in sensitivity to Meth injury in -/- mice may be related to a reduction in VMAT2 expression in these mice. In conclusion, our data suggest that A3R -/- mice are more sensitive to high doses of Meth.

Progression of neurodegeneration and morphologic changes in the brains of juvenile mice with selenoprotein P deleted.

Selenoprotein P (Sepp1) is an important protein involved in selenium (Se) transport and homeostasis. Severe neurologic dysfunction develops in Sepp1 null mice (Sepp1(-/-)) fed a selenium-deficient diet. Sepp1(-/-) mice fed a selenium-deficient diet have extensive degeneration of the brainstem and thalamus, and even when supplemented with selenium exhibit subtle learning deficits and altered basal synaptic transmission and short-term plasticity in the CA1 region of the hippocampus. The goal of this study was to delineate the regional progression of neurodegeneration in the brain, determine the extent of neuronal cell death, and evaluate neurite structural changes within the hippocampus of Sepp1(-/-) mice. Whole brain serial sections of wild-type and Sepp1(-/-) mice maintained on selenium-deficient or supplemented diets over the course of 12 days from weaning were evaluated with amino cupric silver neurodegeneration stain. The neurodegeneration was present in all regions upon weaning and progressed over 12 days in Sepp1(-/-) mice fed selenium-deficient diet, except in the medial forebrain bundle and somatosensory cortex where the neurodegeneration developed post-weaning. The neurodegeneration was predominantly axonal, however the somatosensory cortex and lateral striatum showed silver-stained neurons. Morphologic analysis of the hippocampus revealed decreased dendritic length and spine density, suggesting that loss of Sepp1 also causes subtle changes in the brain that can contribute to functional deficits. These data illustrate that deletion of Sepp1, and presumably selenium deficiency in the brain, produce both neuronal and axonal degeneration as well as more moderate and potentially reversible neurite changes in the developing brain.

Prevention of motor neuron degeneration by novel iron chelators in SOD1(G93A) transgenic mice of amyotrophic lateral sclerosis.

BACKGROUND: The causes of amyotrophic lateral sclerosis (ALS) are largely unknown. Oxidative stress is considered to play a major role in motor neuron degeneration associated with iron homeostasis disturbance. OBJECTIVE: Iron chelation treatment might be a potential therapeutic approach on the basis of its ability to reduce the oxygen free radical generation caused by iron accumulation. METHODS AND RESULTS: In the present study, we applied the brain-permeable iron chelators VK-28 and M30 in a G93A mutant superoxide dismutase 1 transgenic (SOD1(G93A)) mouse model of ALS and found that VK-28 and M30 significantly delayed disease onset, extended the life span and reduced spinal cord motor neuron loss. Furthermore, we documented that both iron chelators significantly attenuated the elevated iron level and transferrin receptor expression, decreased oxygen free radicals and suppressed microglial and astrocytic activation in the spinal cords of the SOD1(G93A) mice. Moreover, we demonstrated that both iron chelators were able to decrease TDP-43 protein aggregation and the proapoptotic molecule Bax, and to enhance antiapoptotic protein Bcl-2 expression, in the ALS mice. CONCLUSIONS: These results provide evidence that iron is involved in the pathogenesis of ALS and iron chelation therapy may have the potential for the prevention and treatment of ALS.

Magnetization transfer MR imaging demonstrates degeneration of the subcortical and cortical gray matter in Huntington disease.

BACKGROUND AND PURPOSE: GM is typically affected in HD since the presymptomatic stage. Our aim was to investigate with MT MR imaging the microstructural changes of the residual brain subcortical and cortical GM in carriers of the HD gene and to preliminarily assess their correlation with the clinical features. MATERIALS AND METHODS: Fifteen HD gene carriers with a range of clinical severity and 15 age- and sex-matched healthy controls underwent MT MR imaging on a 1.5T scanner. The MT ratio was measured automatically in several subcortical and cortical GM regions (striatal nuclei; thalami; and the neocortex of the frontal, temporal, parietal, and occipital lobes) by using FLS tools. RESULTS: The MT ratio was significantly (P < .05 with Bonferroni correction for multiple comparison) decreased in all subcortical structures except the putamen and decreased diffusely in the cerebral cortex of HD carriers compared with controls. Close correlation was observed between the subcortical and cortical regional MT ratios and several clinical variables, including disease duration, motor disability, and scores in timed neuropsychological tests. CONCLUSIONS: MT imaging demonstrates degeneration of the subcortical and cortical GM in HD carriers and might serve, along with volumetric assessment, as a surrogate marker in future clinical trials of HD.