The results reinforce the idea that targeting protein synthesis with small molecules in patients carrying C9ORF72 mutations may result in improved cognitive capacity and reinforce the idea that targeting protein synthesis with small molecules in patients carrying ALS may result in improved cognitive capacity.
Dihydroquercetin (DHQ), a powerful antioxidant and regulator of cellular metabolism, was proposed for therapy of neurodegenerative disorders. Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) are serious neurodegenerative disorders with oxidative stress as an overlapping feature and unmet therapeutic needs. To date, few studies have explored the efficacy of DHQ in animal models of genetically driven neurodegeneration. Here, APPswe/PS1dE9 (APP/PS1) mice and their wild-type (WT) littermates were orally administered DHQ (0.6 mg/kg/day) for four months, starting at eight months of age. At the age of 12 months, behavioral evaluation was performed, followed by brain staining with Congo red for amyloid plaque scoring and immunohistochemical analysis of GFAP-positive cells for the assessment of astrogliosis. Malondialdehyde (MDA) levels in the prefrontal cortex were studied as a marker of oxidative stress. Second, two-month-old FUS[1-359]-Tg mice, which recapitulate the hallmarks of ALS, received DHQ for 1.5 months and were investigated for general physiological parameters, the onset of paralysis, motor functions, and density of motor neurons in the spinal cord. DHQ-treated APPswe/PS1dE9 mutants displayed a decrease in amyloid plaque density of small size (≤100 μm) in the cortex and thalamus, had normalized MDA levels, improved conditioned taste aversion and Y-maze learning, and ameliorated anxiety measures, whereas their hippocampus-dependent step-down and pellet displacement performance remained impaired. In the second study, DHQ-treated FUS[1-359]-Tg mice showed rescued density of spinal cord neurons, normalized liquid and diet intake, and improved coat state, while the onset of paralysis and motor scores were not significantly ameliorated. Thus, chronic administration of low doses of DHQ exerted neuroprotective effects in both AD and ALS genetic models, which partially translated to reduced manifestations of these diseases.
E. Lysikova, K. Sitdikova, Aigerim Makhambetova et al.· Cells· 0 citations
Alzheimer's disease (AD) is a major neurodegenerative disorder characterized by progressive cognitive dysfunction. Necroptosis plays a pertinent role in the neurobiology of AD, which is governed by receptor-interacting protein kinases (RIPK) and mixed lineage kinase domain-like protein (MLKL). Dimethyl fumarate (DMF), a disease-modifying drug used to treat multiple sclerosis, is also known to inhibit necroptosis pathway. Herein, we examined the effect of DMF in C6 cell line and Aβ1-42-induced AD model. DMF treatment reversed the C6 cell viability and expression of RIPK1, RIPK3, and MLKL in lipopolysaccharide model. Intracerebroventricular injection of Aβ1-42 in rats developed the cognitive deficits. Administration of DMF, at 25 and 50 mg/kg doses via peroral route for 14 days, showed a decrease in escape latency and increased exploration of target quadrant Morris water maze test. DMF-recipient rats also displayed exploration of novel object in novel object recognition test, while locomotor activity remained unchanged in open field test. DMF reduced oxidative processes by decreasing lipid peroxidation and increasing catalase and glutathione. Moreover, DMF treatment decreased the levels of IL-6, TNF-α, and CRP cytokines in frontal cortex. A significant downregulation of RIPK1, RIPK3, and MLKL gene expression and protein expression of p-MLKL were observed in the hippocampus following DMF treatment. DMF was also able to improve synaptic plasticity by increasing the expression of synaptophysin, BDNF, MBP, and PSD95, which were determined by using immunoblot. Our results indicate the cognitive improvement and neuroprotective effects of DMF in Aβ1-42 CE model by modulating the necroptosis signalling. We suggest that the selective targeting of necroptosis process may open new treatment avenues for AD.
Sandeep Guin, Aditi Jangli, Manoj P. Dandekar· International Immunopharmaco...· 0 citations
ABSTRACT Alzheimer's disease (AD), a neurodegenerative disorder and the most common cause of dementia, has no cure or effective treatment; thus, identification of disease‐modifying therapeutics is crucial. Nrf2 is a master controller of homeostatic functions whose activity is compromised in AD. Most pharmacological Nrf2 activators are electrophilic molecules that covalently modify cysteine residues in the thiol‐rich Keap1, and many are Michael acceptors, such as low‐molecular‐weight (LMW) skin allergens. However, LMW allergens‐induced Nrf2 activation in a pharmacological setting has only recently attracted attention, exemplified by the clinical success of Dimethyl Fumarate. Hence, we investigated, for the first time, the potential of the skin allergen Isoeugenol to activate Nrf2 and reverse selected AD hallmarks, both in vitro and in vivo, in AD‐specific models. In vitro studies were performed using microglia cells exposed to LPS and neuronal cells overexpressing human APP with Swedish mutation, to evaluate Isoeugenol's potential in decreasing neuroinflammation and activating the Nrf2 pathway, respectively. In vivo studies were conducted in 10‐month‐old AD double‐transgenic mice (APP/PS1), which were intranasally administered Isougenol. Isoeugenol's pharmacokinetic and pharmacodynamic profile, and its effect on mice cognition were evaluated. The results showed that Isoeugenol (1) activated Nrf2 in AD neuronal cells (likely involving AKT signaling); (2) exhibited antioxidant and Nrf2‐dependent anti‐inflammatory activity, which was abolished after Nrf2 silencing; (3) exhibited good pharmacokinetic and pharmacodynamic profiles; (4) reduced the levels of Aβ peptides in vitro and in vivo; (5) reduced triglyceride and LDL cholesterol levels in treated mice; and (6) improved the memory deficits in old mice. This is the first study reporting Isoeugenol's intranasal administration, and on specific AD mice models. Overall, the results reinforce Isoeugenol as a pleiotropic molecule, with great potential for AD treatment.
Ana Silva, Sónia Silva, Jéssica Macedo et al.· The FASEB Journal· 0 citations
Objective T cells are increased in the brain in Alzheimer’s disease (AD) and primary tauopathies where they correlate with tau pathology. In mouse models, T cells exacerbate tau-related neuroinflammation and neurodegeneration, and depletion of T cells is neuroprotective. Here, we investigate whether the multiple sclerosis drug fingolimod may inhibit infiltration of T cells into the brain in the setting of tau pathology and thereby attenuate tau-mediated neurodegeneration. Methods P301S-tau transgenic mice expressing human APOE4 (TE4), which develop tau pathology, neurodegeneration, and neuroinflammation with T cell accumulation, were randomly assigned to receive 1 mg/kg/d fingolimod in drinking water or standard mouse drinking water beginning just prior to the accumulation of neurofibrillary tangle pathology at 6 months of age. Mice were then assessed with a battery of cognitive behavioral assays at 9 months of age and euthanized at 9.5 months of age to analyze the blood and brain using flow cytometry, single molecule array (SIMOA) technology, stereotactic brain measurements, and immunohistochemistry. Results Fingolimod produced the expected lymphopenia in peripheral blood but unexpectedly exacerbated brain T cell accumulation, microgliosis, astrogliosis, and tau pathology, with no significant effect on neurodegeneration or behavioral impairment in TE4 mice. Interpretation These results indicate fundamental differences in the nature of the adaptive immune response to tau pathology versus other neuroinflammatory diseases such as multiple sclerosis and underscores the importance of understanding the impact of immune modulating therapies on all aspects of AD-related pathology in preclinical models prior to consideration and initiation of clinical trials.
M. Rudman, Alexandra Litvinchuk, Cathryn Smith et al.· bioRxiv· 0 citations
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition and cognitive decline. Clinical evidence indicates that Hericium erinaceus whole fruiting body powder offers limited therapeutic efficacy, which is suggested to be constrained by whole-food matrix interference and uncertainties in central nervous system (CNS) exposure. Therefore, we hypothesized that erinacine C (EC)—a purified active component from Hericium erinaceus mycelia—could resolve these limitations and potentially exhibit favorable neuroprotective effects owing to its low molecular weight and lipophilicity. In this study, we investigated the neuroprotective potential and associated signaling alterations of EC using APP/PS1 transgenic mice and Aβ25-35-induced PC12 cells. In vivo, oral administration of EC alleviated deficits in activities of daily living, as evidenced by improvements in nesting and burrowing behaviors, along with enhanced short-term spatial memory in the Y-maze test. EC treatment was associated with a reduction in hippocampal Aβ plaque accumulation, suppression of glial activation (GFAP and IBA1), and decreased IL-6 levels in both serum and hippocampal tissues. In vitro, EC intervention counteracted Aβ25-35-induced cytotoxicity in PC12 cells. Analysis of signaling markers revealed that EC treatment was accompanied by a restoration of p-Akt/Akt levels and a suppression of p-GSK3β (Tyr216) activation. Consequently, EC treatment was correlated with reduced tau hyperphosphorylation, the up-regulation of the anti-apoptotic protein Bcl-2, and the down-regulation of pro-apoptotic markers including Bax and cleaved-caspase-3, thereby lowering the total apoptotic rate. Taken together, these findings suggest that EC may mitigate cognitive impairment and neurodegeneration in parallel with alterations in the Akt/GSK3β/tau/caspase-3 signaling response, thereby representing a potentially promising therapeutic candidate for the intervention of AD.
Neuroprotective effects of statins in Parkinson’s disease (PD) remain uncertain, and their activity in genetic α-synuclein (αSyn) disease models has been insufficiently characterized. We evaluated atorvastatin (ATO) in a mouse model with nigral overexpression of human A53T-mutant αSyn. Mice received ATO by oral gavage at 10 mg/kg/day for 5 weeks and were assessed using behavioral testing, neuropathological assessment, brain transcriptomics, and molecular docking. ATO inhibited cholesterol biosynthesis-related transcriptional programs and broadly remodeled lipid metabolism-associated networks, but did not lead to functional or histopathological benefit. ATO did not ameliorate motor deficits, restore dopaminergic markers, or reduce αSyn protein levels or pSer129-αSyn immunoreactivity. Transcriptomic analysis further showed that ATO failed to reverse the core disease-associated signature induced by A53T αSyn overexpression and instead increased SNCA mRNA. Targeted RNA-seq and western blot analyses showed no parallel increase in Prkn, Gba1, or Lamp2 transcript abundance or in PARKIN, GBA1, or LAMP2A protein expression. Molecular docking, used here as an exploratory structural comparison, suggested a relatively weak predicted interaction between ATO and αSyn when compared with several other statins and provided supportive context for the lack of efficacy. Overall, our findings indicate limited efficacy of ATO in this αSyn-driven setting and support further comparative evaluation of individual statins across complementary PD models.
Li-Jian Wei, Jun-Kai Hua, Shu Tang et al.· Neurotoxicity research· 0 citations
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