Effects of Memantine and High Dose Vitamin D on Gait in Male APP/PS1 Alzheimer’s Disease Mice Following Vitamin D Deprivation

Background: Altered gait is a frequent feature of Alzheimer’s disease (AD), as is vitamin D deficiency. Treatment with memantine and vitamin D can protect cortical axons from exposure to amyloid-β and glutamate toxicity, suggesting this combination may mitigate altered gait in AD. Objective: Investigate the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait performance in APPswe/PS1dE9 mice. Methods: Male APPswe/PS1dE9 mice were split into four groups (n = 14 each) at 2.5 months of age. A control group was fed a standard diet throughout while the other three groups started a vitamin D-deficient diet at month 6. One group remained on this deficient diet for the rest of the study. At month 9, the other two groups began treatment with either memantine alone or memantine combined with 10 IU/g of vitamin D. Gait was assessed using CatWalk at months 6, 9, 12, and 15. Results: Vitamin D deprivation led to a 13% increase in hind stride width by month 15 (p < 0.001). Examination of the treatment groups at month 15 revealed that mice treated with memantine alone still showed an increase in hind stride width compared to controls (p < 0.01), while mice treated with memantine and vitamin D did not (p = 0.21). Conclusion: Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD.

Effects of memantine and high dose vitamin D on gait in the APP/PS1 mouse model of Alzheimer's disease following vitamin D deprivation

Background: Altered gait is a frequent feature of Alzheimer's disease (AD), as is vitamin D deficiency. Treatment with memantine and vitamin D can protect cortical axons from exposure to amyloid-β and glutamate toxicity, suggesting this combination may mitigate altered gait in AD. Objective: Investigate the effects of vitamin D deprivation and subsequent treatment with memantine and vitamin D enrichment on gait performance in APPswe/PS1dE9 mice. Methods: Male APPswe/PS1dE9 mice were split into four groups (n=14 each) at 2.5 months of age. A control group was fed a standard diet throughout while the other three groups started a vitamin D-deficient diet at month 6. The VitD- group remained on this deficient diet for the rest of the study. At month 9, the remaining two groups began treatment with either memantine alone or memantine combined with 10 IU/g of vitamin D. Gait performance was assessed at months 6, 9, 12, and 15. Results: Vitamin D deprivation led to a 13% increase in hind stride width by month 15 (p<0.001). Examination of the treatment groups at month 15 revealed that mice treated with memantine alone still showed an increase in hind stride width compared to controls (p<0.01), while mice treated with memantine and vitamin D did not (p=0.21). Conclusion: Vitamin D deprivation led to impaired postural control in the APPswe/PS1dE9 model. Treatment with memantine and vitamin D, but not memantine alone, prevented this impairment. Future work should explore the potential for treatments incorporating vitamin D supplementation to improve gait in people with AD.

Hibiscus sabdariffa extract protects HT-22 cells from glutamate-induced neurodegeneration by upregulating glutamate transporters and exerts lifespan extension in C. elegans via DAF-16 mediated pathway

BACKGROUND: Glutamate toxicity is involved in several neurodegenerative conditions, including Alzheimer’s disease. OBJECTIVE: The study aims to investigate the neuroprotective efficacy of ethanol extract of Hibiscus sabdariffa calyces (HS) against glutamate-induced toxicity in HT-22 cells and induce anti-aging property in Caenorhabditis elegans. METHODS: HT-22 cells were pre-treated with HS followed by glutamate and evaluated for the neuroprotective effect using cell viability assay, confocal microscopic analysis, qPCR, Western blot, and docking analysis. Induction of anti-aging property in C. elegans with HS extract was analyzed through physiological assays and qPCR analysis. RESULTS: GC-MS analysis of the HS extract showed the presence of 19 compounds with antioxidant properties including oleamide,2-(diethoxymethyl)furan and 5-methylfurfural. In vitro studies reveal that glutamate exerted toxicity in HT-22 cells by inducing oxidative stress, depleting glutathione, downregulating glutamate transporters, antioxidant genes, inducing autophagy (Beclin-1, Atg-5, Atg-7, LC3-II) by the activation of MAPK (p38, JNK) pathway, and causing apoptosis. However, pre-treatment with HS extract (5, 10μg/ml) reversed the effect and offered neuroprotection. In silico studies showed that the compounds of HS extract can bind effectively and inhibit the activity of NMDAR, calpain-1 and GSK-3β. In C. elegans, HS extended lifespan, reduced the accumulation of lipofuscin, modulated healthspan-related genes and downregulated the expression of daf-2. CONCLUSION: Our results indicate that HS with its bioactive components exhibits neuroprotective activity by upregulating glutamate transporters, inhibiting autophagy and exerts anti-aging property through DAF-16 dependent mechanism.

Is impaired energy production a novel insight into the pathogenesis of pyridoxine-dependent epilepsy due to biallelic variants in ALDH7A1?

Background Pyridoxine-dependent epilepsy (PDE) is due to biallelic variants in ALDH7A1 (PDE-ALDH7A1). ALDH7A1 encodes α-aminoadipic semialdehyde dehydrogenase in lysine catabolism. We investigated the gamma aminobutyric acid (GABA) metabolism and energy production pathways in human PDE-ALDH7A1 and its knock-out aldh7a1 zebrafish model. Methods We measured GABA pathway, and tricarboxylic acid cycle metabolites and electron transport chain activities in patients with PDE-ALDH7A1 and in knock-out aldh7a1 zebrafish. Results We report results of three patients with PDE-ALDH7A1: low paired complex I+II and complex II+III and individual complex IV activities in muscle biopsy in patient 1 (likely more severe phenotype); significantly elevated CSF glutamate in the GABA pathway and elevated CSF citrate, succinate, isocitrate and α-ketoglutarate in the TCA cycle in patient 3 (likely more severe phenotype); and normal CSF GABA pathway and TCA cycle metabolites on long-term pyridoxine therapy in patient 2 (likely milder phenotype). All GABA pathway metabolites (γ-hydroxybutyrate, glutamine, glutamate, total GABA, succinic semialdehyde) and TCA cycle metabolites (citrate, malate, fumarate, isocitrate, lactate) were significantly low in the homozygous knock-out aldh7a1 zebrafish compared to the wildtype zebrafish. Homozygous knock-out aldh7a1 zebrafish had decreased electron transport chain enzyme activities compared to wildtype zebrafish. Discussion We report impaired electron transport chain function, accumulation of glutamate in the central nervous system and TCA cycle dysfunction in human PDE-ALDH7A1 and abnormal GABA pathway, TCA cycle and electron transport chain in knock-out aldh7a1 zebrafish. Central nervous system glutamate toxicity and impaired energy production may play important roles in the disease neuropathogenesis and severity in human PDE-ALDH7A1.

Datumetine Preferentially Upregulates NMDAR Signalling Pathways in Different Brain Regions of Mice

Background: We earlier reported that datumetine possesses binding affinity with NMDAR and that 14-day exposure to datumetine altered NMDAR signalling by mimicking glutamate toxicity. Here, we investigated the potential neuroprotective effect of a single shot of a low dose of datumetine administration in BALB/c mice. Results: Relative to Veh, datumetine downregulate the expression of CamKIIα in the hippocampus and PFC but not in the cerebellum, CREB was also upregulated in the PFC only, but pCREB was also upregulated in all the three brain regions observed, while BDNF was only upregulated in both hippocampus and PFC of Datumetine relative to Veh. MK-801 on the other hand reversed some of the effects of datumetine in the brain regions observed. No major histological alterations were observed in the different brain regions immunohistochemically. Conclusion: We conclude that a single low dose of datumetine moderately enhances NMDAR activity. This showed the neuroprotective potentials of low datumetine exposure.