calpain and Cognitive-Dysfunction

Overstimulation of N-methyl-D-aspartate receptors (NMDARs) is the leading cause of brain excitotoxicity and often contributes to neurodegenerative diseases such as Alzheimer's Disease (AD), the most common form of dementia. This study aimed to evaluate a new NMDA receptor antagonist (UB-ALT-EV) and memantine in 6-month-old female 5XFAD mice that were exposed orally to a chronic low-dose treatment. Behavioral and cognitive tests confirmed better cognitive performance in both treated groups. Calcium-dependent protein calpain-1 reduction was found after UB-ALT-EV treatment but not after memantine. Changes in spectrin breakdown products (SBDP) and the p25/p35 ratio confirmed diminished calpain-1 activity. Amyloid β (Aβ) production and deposition was evaluated in 5XFAD mice and demonstrated a robust effect of NMDAR antagonists on reducing Aβ deposition and the number and size of Thioflavin-S positive plaques. Furthermore, glycogen synthase kinase 3β (GSK3β) active form and phosphorylated tau (AT8) levels were diminished after UB-ALT-EV treatment, revealing tau pathology improvement. Because calpain-1 is involved in autophagy activation, autophagic proteins were studied. Strikingly, results showed changes in the protein levels of unc-51-like kinase (ULK-1), beclin-1, microtubule-associated protein 1A/1B-light chain 3(LC3B-II)/LC3B-I ratio, and lysosomal-associated membrane protein 1 (LAMP-1) after NMDAR antagonist treatments, suggesting an accumulation of autophagolysosomes in 5XFAD mice, reversed by UB-ALT-EV. Likewise, treatment with UB-ALT-EV recovered a WT mice profile in apoptosis markers Bcl-2, Bax, and caspase-3. In conclusion, our results revealed the potential neuroprotective effect of UB-ALT-EV by attenuating NMDA-mediated apoptosis and reducing Aβ deposition and deposition jointly with the autophagy rescue to finally reduce cognitive alterations in a mice model of familial AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autophagy; Calpain; Cognitive Dysfunction; Female; Memantine; Mice; Mice, Transgenic; Receptors, N-Methyl-D-Aspartate

Diabetes mellitus (DM) has been considered an accelerator of Alzheimer's disease (AD), but the cellular and molecular mechanisms underlying this effect are not fully understood. Here, we attempted to determine the role and regulatory mechanism of calpain in the AD-like cognitive decline and pathological changes in rats caused by DM. In the initial stages, our results verified that DM model rats showed cognitive impairment, as well as a loss of neurons, decreased pericyte marker (PDGFR-β and α-SMA), and calpain-2 expression and amyloid-β (Aβ) deposition in the hippocampal tissues. In high glucose-induced primary pericytes, the cell apoptotic rate was increased, and cell proliferation was inhibited in a time-dependent manner. The protein level of calpain-2 was also upregulated by HG induction, but the level of calpain-1 did not change with HG treatment, which was also observed in DM model rats. Subsequently, some DM model rats were administered calpeptin, an inhibitor of calpain. Our data revealed that calpeptin treatment significantly suppressed calpain-1 and calpain-2 expression in the hippocampal tissues and effectively improved the cognitive impairments of DM model rats. Neuronal loss, Aβ accumulation, pericyte loss, inflammation, and oxidative stress injury in the hippocampal tissues of DM model rats were also partly rescued by calpeptin administration. Our work demonstrated that the calpain inhibitor calpeptin could alleviate DM-induced AD-like cognitive impairments and pathological changes in rats, and this effect may be associated with pericytes. Calpeptin may become a promising drug to treat the AD-like complications of DM.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Calpain; Cognitive Dysfunction; Diabetes Mellitus; Dipeptides; Glucose; Glycoproteins; Rats

Postoperative cognitive dysfunction (POCD) is a common phenomenon among elderly patients with unclear etiology. Sterile alpha and TIR motif-containing 1 (Sarm1) plays important roles in neuroinflammation and cognitive function, and activates Calpain which has been shown to promote POCD through TrkB cleavage. This study aims to test the hypothesis that Sarm1 is involved in POCD through regulating Calpain activity. Wild type and Sarm1 knock out mice were exposed to isoflurane. Mouse cognitive function was determined by Morris water maze test. Neuroinflammation was determined by Iba1 and GFAP protein levels and mRNA expression of proinflammatory cytokines. Calpain activation was determined by αII-spectrin degradation and TrkB cleavage. Mitogen-activated protein kinase (MAPK) signaling was determined by c-Jun N-terminal kinase and cJun phosphorylation both in vivo and in vitro by Western blot and immunofluorescence staining. We found that Sarm1 deletion suppressed isoflurane induced cognitive impairment and neuroinflammation. Deletion of Sarm1 inhibited isoflurane induced αII-spectrin degradation and TrkB cleavage, which indicates suppression of Calpain activation. Finally, deletion of Sarm1 suppressed isoflurane induced MAPK signaling both in vivo and in vitro. Our findings suggest that isoflurane anesthesia induced cognitive impairment is prevented by Sarm1 deletion in mice, making Sarm1 a potent therapeutic target for treating or preventing POCD.

Topics: Aged; Anesthesia; Animals; Armadillo Domain Proteins; Calpain; Cognitive Dysfunction; Cytoskeletal Proteins; Humans; Isoflurane; Mice; Neuroinflammatory Diseases; Postoperative Cognitive Complications; Spectrin

Topics: Alzheimer Disease; Animals; Calpain; Chromosome Pairing; Cognitive Dysfunction; Disease Models, Animal; Ginsenosides; Glycogen Synthase Kinase 3 beta; Hippocampus; Insulin Receptor Substrate Proteins; Male; Maze Learning; Morris Water Maze Test; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Streptozocin; tau Proteins

Postoperative cognitive dysfunction (POCD) is an impairment of cognition that affects post-surgery patients. Sevoflurane anesthesia is linked to cognitive dysfunction correlated to the expression of miRNA levels.. In the current study, we investigated if miR-124 can offer protection against cognitive deficits induced by sevoflurane in a spatial learning paradigm, and examined the molecular mechanisms through cell cultures.. Escape latency, platform crossings in probe trials and swimming speed in the Morris water maze in sevoflurane-treated mice were utilized as a measure of cognitive function. The relative miR-124 expression, and mRNA expressions of Bax, caspase-3 and Bcl-2 in sevoflurane-treated hippocampal cultures were measured using real-time quantitative polymerase chain reaction (RT-qPCR). Moreover, the changes in interleukin (IL)-1β, tumor necrosis factor alpha (TNF-α) and IL-6 were determined using enzyme-linked immunosorbent assay (ELISA). The binding between miR-124 and calpain small subunit 1 (Capn4) was verified with site-directed mutagenesis. The involvement of the nuclear factor kappa B (NF-κB) signaling pathway was examined using western blot analysis.. Our findings indicated that the miR-124 expression was inhibited by sevoflurane treatment in live rats and mouse hippocampal neurons to prevent apoptosis and inflammatory responses. We confirmed Capn4 as a target of miR-124. Treatment with sevoflurane enhanced the expression of Capn4, while overexpression of miR124 suppressed the enhanced expression of Capn4. Also, miR-124 inhibited apoptosis in murine hippocampal neurons induced by sevoflurane via the NF-κB signaling pathway.. Our findings demonstrated that miR-124 exerted its neuroprotective role against sevoflurane via targeting Capn4 and NF-κB signaling pathways. Our work may provide a novel and efficacious treatment for sevoflurane anesthesia-related cognitive dysfunction.

Topics: Anesthesia; Animals; Apoptosis; Calpain; Cognitive Dysfunction; Humans; Mice; MicroRNAs; NF-kappa B; Rats; Sevoflurane; Signal Transduction

During brain development, volatile anesthetic can rapidly interfere with physiologic patterns of dendritic development and synaptogenesis and impair the formation of precise neuronal circuits. KCC2 plays vital roles in spine development and synaptogenesis through its Cl- transport function and structural interactions with the spine cytoskeleton protein 4.1 N. The aim of this study was to dissect the mechanism of volatile anesthetics, which impair dendritic development and synaptogenesis via mediation of KCC2 cleavage.. Westernblotting was employed to assess the expression change of NR2B, NR2A, calpain-1, calpain-2, KCC2, and 4.1 N protein of rat (PND 5). Co-immunoprecipitation was applied to demonstrate the interaction between KCC2 and 4.1 N protein. Long-term cognitive deficiency was assessed by MWM. Lentivirus-calpain-2 was administered by hippocampus stereotaxic injection.. There was a significant increase in the level of NR2B instead of NR2A exposure to isoflurane. Calpain-2 was excessively activated via NR2B after 6 h of isoflurane exposure. The expression of plasmalemmal KCC2 and 4.1 N protein was significantly decreased treated with isoflurane. The isoflurane group showed longer traveled distance, prolonged escape latency, less time spent in the target quadrant, and decreased platform crossings. Pretreatment with ifenprodil and downregulated calpain-2 expression significantly alleviated these neurotoxicity responses and cognitive deficiency after isoflurane exposure.. A significant increase in NR2B, excessive activation of calpain-2 and increased cleavage of plasmalemmal KCC2, are involved in isoflurane-induced neurotoxicity and long-term cognitive deficiency. Blocking NR2B and calpain-2 activity significantly attenuated these responses. The KCC2 cleavage mediated by NR2B and calpain-2 is a major determinant of isoflurane-induced long-term cognitive deficiency.

Topics: Animals; Brain; Calpain; Cognitive Dysfunction; Isoflurane; K Cl- Cotransporters; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spatial Memory; Symporters

Topics: Animals; Blood Glucose; Calpain; Cognitive Dysfunction; Cyclin-Dependent Kinase 5; Diabetes Complications; Diabetes Mellitus, Experimental; Dipeptides; Gene Expression Regulation, Enzymologic; Glucose; Hippocampus; Mice; Phosphotransferases

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by aberrant tau protein hyperphosphorylation, which eventually leads to the formation of neurofibrillary tangles. Hyperphosphorylated tau protein is considered as a vital factor in the development of AD and is highly associated with cognitive impairment. Therefore, it is recognized to be a potential therapeutic target. Quercetin (QUE) is a naturally occurring flavonoid compound. In the present study, the inhibitory effect of QUE on okadaic acid (OA)-induced tau protein hyperphosphorylation in HT22 cells was explored. Western blotting results indicated that QUE significantly attenuated OA‑induced tau protein hyperphosphorylation at the Ser396, Ser199, Thr231 and Thr205 sites. Further experiments demonstrated that QUE inhibited the activity of cyclin‑dependent kinase 5 (CDK5), a key enzyme in the regulation of tau protein, and blocked the Ca2+‑calpain‑p25‑CDK5 signaling pathway. These observations indicate the ability of QUE to decrease tau protein hyperphosphorylation and thereby attenuate the associated neuropathology. In conclusion, these results support the potential of QUE as a therapeutic agent for AD and other neurodegenerative tauopathies.

Topics: Alzheimer Disease; Calcium; Calpain; Cognitive Dysfunction; Cyclin-Dependent Kinase 5; Hippocampus; Humans; Nerve Tissue Proteins; Neurons; Okadaic Acid; Phosphorylation; Quercetin; tau Proteins

Modern sedentary lifestyle with altered dietary habits imposes the risk of human health towards several metabolic disorders such as obesity. The metabolic insults negatively affect the mental health status and quality life of affected individuals. Melatonin is a potent antioxidant with anti-inflammatory and neuroprotective properties. The aim of the present study was to investigate the protective effect of melatonin on the cognitive and neurochemical deficits induced by the high-fat diet (HFD) and alcohol (ALC) alone or in combination (HFD + ALC) in rats. Male Wistar rats were given ALC (3-15% i.e. increased gradually) and HFD for 12 weeks in different experimental groups. After 12 weeks, we found that simultaneous consumption of HFD and ALC exacerbates cognitive dysfunction and neurochemical anomalies. However, melatonin (10 mg/kg/day, i.p.) treatment for four weeks significantly prevented memory deficits, oxidative stress and neuroinflammation in HFD, ALC and HFD + ALC groups. RT-PCR analysis showed down-regulation of nuclear factor erythroid 2-related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) in ALC and HFD + ALC groups. Moreover, caspase-3 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) mRNA expression level were found up-regulated in hippocampus of HFD, ALC and HFD + ALC groups. However, calpain expression was found up-regulated only in the hippocampus of HFD + ALC group. Chronic treatment with melatonin significantly restored the aberrant gene expression level in HFD, ALC and HFD + ALC group. In conclusion, our findings indicated that melatonin can mitigate the HFD and ALC-induced cognitive deficits via attenuation of oxidative stress and calpain-1 dependent as well as independent caspase-3 mediated neuronal cell death.

Topics: Acetylcholinesterase; Alcohol Drinking; Animals; Apoptosis; Calpain; Caspase 3; Cognitive Dysfunction; Diet, High-Fat; Hippocampus; Male; Melatonin; NF-kappa B; Oxidative Stress; Rats; Rats, Wistar