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Aging Oct 2023The NLRP3 inflammasome is involved in the neuroinflammatory pathway of Alzheimer's disease (AD). The aim of this study is to explore the roles and underlying mechanisms...
The NLRP3 inflammasome is involved in the neuroinflammatory pathway of Alzheimer's disease (AD). The aim of this study is to explore the roles and underlying mechanisms of ginkgolide (Baiyu®) on amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice and a murine microglial cell line, BV-2. In the present study, the APP/PS1 mice were administered with ginkgolide, followed by a Morris water maze test. The mice were then euthanized to obtain brain tissue for histological and Aβ analysis. Additionally, BV-2 cells were pretreated with ginkgolide and then incubated with Aβ1-42 peptide. NLRP3, ASC, and caspase-1 mRNA and protein expression in brain tissue of mice and BV-2 cells were quantified by real-time PCR and western blotting, as well as reactive oxygen species (ROS) production, interleukin (IL)-1β and IL-18 levels by lucigenin technique and ELISA. Compared with the APP/PS1 mice, ginkgolide-treated mice demonstrated the shortened escape latency, reduced plaques, less inflammatory cell infiltration and neuron loss in the hippocampi of APP/PS1 mice. The levels of NLRP3, ASC, caspase-1, ROS, IL-1β, and IL-18 were also decreased in the brain tissue of APP/PS1 mice or Aβ1-42-treated BV-2 cells following ginkgolide treatment. Ginkgolide exerted protective effects on AD, at least partly by inactivating the NLRP3/caspase-1 pathway.
Topics: Animals; Mice; Alzheimer Disease; NLR Family, Pyrin Domain-Containing 3 Protein; Interleukin-18; Amyloid beta-Peptides; Neuroinflammatory Diseases; Reactive Oxygen Species; Caspase 1; Amyloid beta-Protein Precursor; Memory Disorders; Mice, Transgenic; Disease Models, Animal
PubMed: 37793010
DOI: 10.18632/aging.205072 -
Frontiers in Neuroscience 2023Post-traumatic stress disorder (PTSD) is a stress-associated complex and debilitating psychiatric disorder due to an imbalance of neurotransmitters in response to... (Review)
Review
Post-traumatic stress disorder (PTSD) is a stress-associated complex and debilitating psychiatric disorder due to an imbalance of neurotransmitters in response to traumatic events or fear. PTSD is characterized by re-experiencing, avoidance behavior, hyperarousal, negative emotions, insomnia, personality changes, and memory problems following exposure to severe trauma. However, the biological mechanisms and symptomatology underlying this disorder are still largely unknown or poorly understood. Considerable evidence shows that PTSD results from a dysfunction in highly conserved brain systems involved in regulating stress, anxiety, fear, and reward circuitry. This review provides a contemporary update about PTSD, including new data from the clinical and preclinical literature on stress, PTSD, and fear memory consolidation and extinction processes. First, we present an overview of well-established laboratory models of PTSD and discuss their clinical translational value for finding various treatments for PTSD. We then highlight the research progress on the neural circuits of fear and extinction-related behavior, including the prefrontal cortex, hippocampus, and amygdala. We further describe different molecular mechanisms, including GABAergic, glutamatergic, cholinergic, and neurotropic signaling, responsible for the structural and functional changes during fear acquisition and fear extinction processes in PTSD.
PubMed: 38116070
DOI: 10.3389/fnins.2023.1281401 -
Translational Neurodegeneration Nov 2023Synaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs...
BACKGROUND
Synaptic degeneration occurs in the early stage of Alzheimer's disease (AD) before devastating symptoms, strongly correlated with cognitive decline. Circular RNAs (circRNAs) are abundantly enriched in neural tissues, and aberrant expression of circRNAs precedes AD symptoms, significantly correlated with clinical dementia severity. However, the direct relationship between circRNA dysregulation and synaptic impairment in the early stage of AD remains poorly understood.
METHODS
Hippocampal whole-transcriptome sequencing was performed to identify dysregulated circRNAs and miRNAs in 4-month-old wild-type and APP/PS1 mice. RNA antisense purification and mass spectrometry were utilized to unveil interactions between circRIMS2 and methyltransferase 3, N6-adenosine-methyltransferase complex catalytic subunit (METTL3). The roles of circRIMS2/miR-3968 in synaptic targeting of UBE2K-mediated ubiquitination of GluN2B subunit of NMDA receptor were evaluated via numerous lentiviruses followed by morphological staining, co-immunoprecipitation and behavioral testing. Further, a membrane-permeable peptide was used to block the ubiquitination of K1082 on GluN2B in AD mice.
RESULTS
circRIMS2 was significantly upregulated in 4-month-old APP/PS1 mice, which was mediated by METTL3-dependent N6-methyladenosine (m6A) modification. Overexpression of circRIMS2 led to synaptic and memory impairments in 4-month-old C57BL/6 mice. MiR-3968/UBE2K was validated as the downstream of circRIMS2. Elevated UBE2K induced synaptic dysfunction of AD through ubiquitinating K1082 on GluN2B. Silencing METTL3 or blocking the ubiquitination of K1082 on GluN2B with a short membrane-permeable peptide remarkably rescued synaptic dysfunction in AD mice.
CONCLUSIONS
In conclusion, our study demonstrated that m6A-modified circRIMS2 mediates the synaptic and memory impairments in AD by activating the UBE2K-dependent ubiquitination and degradation of GluN2B via sponging miR-3968, providing novel therapeutic strategies for AD.
Topics: Animals; Mice; Adenosine; Alzheimer Disease; Memory Disorders; Methyltransferases; Mice, Inbred C57BL; Mice, Transgenic; MicroRNAs; Peptides; Receptors, N-Methyl-D-Aspartate; RNA, Circular
PubMed: 38012808
DOI: 10.1186/s40035-023-00386-6 -
Psychopharmacology Jul 2023For most psychiatric conditions, including alcohol use disorder (AUD), FDA-approved pharmacological treatments are limited and their efficacy is restricted to only...
BACKGROUND
For most psychiatric conditions, including alcohol use disorder (AUD), FDA-approved pharmacological treatments are limited and their efficacy is restricted to only certain subgroups of patients. Scientific interest in the potential of psychedelic drugs has dramatically increased because of clinical preliminary evidence of efficacy in treating various psychiatric disorders. One of the most promising compounds belonging to this class of molecules is psilocybin. Here, to elucidate the therapeutic potential and treatment modalities of this drug, we investigated the effect of psilocybin on alcohol drinking and seeking in genetically selected Marchigian Sardinian alcohol-preferring (msP) rats, a well validated animal model of AUD characterized by excessive drinking and seeking.
METHODS
Using male and female msP rats, we tested the effect of psilocybin on home cage voluntary alcohol consumption. We also tested the effect of the drug on the alcohol deprivation effect (ADE) model of relapse and on cue-induced reinstatement of alcohol seeking after a period of abstinence. Finally, we evaluated if psilocybin may disrupt the reconsolidation process of alcohol-related memory.
RESULTS
Psilocybin did not reduce alcohol consumption, nor it prevented increased alcohol drinking after a period of forced abstinence and cue-induced reinstatement of alcohol-seeking. Noteworthy, in a memory retrieval-reconsolidation paradigm, psilocybin markedly attenuated resumption of alcohol seeking.
CONCLUSIONS
Altogether these data suggest that, despite psilocybin does not affect alcohol drinking and relapse, it may be highly effective if used to block the reconsolidation process of alcohol-related memories. This opens to the possibility of using this psychedelic drug in clinical settings in which AUD patients undergo procedures to recall the memory of alcohol and are then treated with psilocybin during the memory reconsolidation phase.
Topics: Rats; Male; Female; Animals; Psilocybin; Hallucinogens; Memory; Ethanol; Recurrence
PubMed: 37266686
DOI: 10.1007/s00213-023-06384-w -
Behavioral Sciences (Basel, Switzerland) Sep 2023Over the last several decades, both brain electrophysiological measurements, such as electroencephalogram (EEG) and event-related potentials/oscillations (ERPs/EROs),...
Over the last several decades, both brain electrophysiological measurements, such as electroencephalogram (EEG) and event-related potentials/oscillations (ERPs/EROs), and neuroimaging measures have immensely contributed to our understanding of neural mechanisms underlying various psychiatric disorders, including alcohol use disorder (AUD). This Special Issue was launched to invite research and review articles that explore the utility of these neural measures to determine the effects of alcohol use (e.g., regular drinking, social drinking, binge/heavy drinking, and chronic drinking) on brain structure and function and/or to predict risk for developing AUD and other outcomes (e.g., other drug use and externalizing/internalizing traits) across various demographic characteristics (age, gender, ethnicity, etc.). We received seven scholarly articles, each dealing with specialized topics, which contribute to enhancing our understanding of the brain mechanisms underlying AUD and its risk. The titles of the contributing articles are: (i) Random Forest Classification of Alcohol Use Disorder Using EEG Source Functional Connectivity, Neuropsychological Functioning, and Impulsivity Measures; (ii) Delta Event-Related Oscillations Are Related to a History of Extreme Binge Drinking in Adolescence and Lifetime Suicide Risk; (iii) Alcohol Use and Prefrontal Cortex Volume Trajectories in Young Adults with Mood Disorders and Associated Clinical Outcomes; (iv) Statistical Nonparametric fMRI Maps in the Analysis of Response Inhibition in Abstinent Individuals with History of Alcohol Use Disorder; (v) Differentiating Individuals with and without Alcohol Use Disorder Using Resting-State fMRI Functional Connectivity of Reward Network, Neuropsychological Performance, and Impulsivity Measures; (vi) Epigenetic Effects in HPA Axis Genes Associated with Cortical Thickness, ERP Components and SUD Outcome; and (vii) Predicting Alcohol-Related Memory Problems in Older Adults: A Machine Learning Study with Multi-Domain Features. This Special Issue contains a range of useful topics, covering the utility of EEG, MRI, neuropsychology, epigenetics, environmental, behavioral, and clinical measures related to outcomes, and biological risks related to AUD, which will be useful to alcohol researchers around the world.
PubMed: 37887440
DOI: 10.3390/bs13100790 -
Nutrients Dec 2023Alzheimer's disease (AD), is a progressive neurodegenerative disorder that involves the deposition of β-amyloid plaques and the clinical symptoms of confusion, memory...
Alzheimer's disease (AD), is a progressive neurodegenerative disorder that involves the deposition of β-amyloid plaques and the clinical symptoms of confusion, memory loss, and cognitive dysfunction. Despite enormous progress in the field, no curative treatment is available. Therefore, the current study was designed to determine the neuroprotective effects of N-methyl-(2S, 4R)-Trans-4-hydroxy-L-proline (NMP) obtained from Sideroxylon obtusifolium, a Brazilian folk medicine with anti-inflammatory and anti-oxidative properties. Here, for the first time, we explored the neuroprotective role of NMP in the Aβ-injected mouse model of AD. After acclimatization, a single intracerebroventricular injection of Aβ (5 µL/5 min/mouse) in C57BL/6N mice induced significant amyloidogenesis, reactive gliosis, oxidative stress, neuroinflammation, and synaptic and memory deficits. However, an intraperitoneal injection of NMP at a dose of (50 mg/kg/day) for three consecutive weeks remarkably decreased beta secretase1 (BACE-1) and Aβ, activated the astrocyte and microglia expression level as well as downstream inflammatory mediators such as pNF-ĸB, TNF-α, and IL-1β. NPM also strongly attenuated oxidative stress, as evaluated by the expression level of NRF2/HO-1, and synaptic failure, by improving the level of both the presynaptic (SNAP-25 and SYN) and postsynaptic (PSD-95 and SNAP-23) regions of the synapses in the cortexes and hippocampi of the Aβ-injected mice, contributing to cognitive improvement in AD and improving the behavioral deficits displayed in the Morris water maze and Y-maze. Overall, our data suggest that NMP provides potent multifactorial effects, including the inhibition of amyloid plaques, oxidative stress, neuroinflammation, and cognitive deficits.
Topics: Mice; Animals; Alzheimer Disease; Neuroprotective Agents; Neuroinflammatory Diseases; Plaque, Amyloid; Mice, Inbred C57BL; Amyloid beta-Peptides; Memory Disorders; Disease Models, Animal
PubMed: 38068844
DOI: 10.3390/nu15234986 -
Journal of Psychosomatic Research Oct 2023Functional cognitive disorder (FCD) accounts for around a third of patients attending specialized memory clinics. It is also overrepresented in patients with other... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Functional cognitive disorder (FCD) accounts for around a third of patients attending specialized memory clinics. It is also overrepresented in patients with other functional and somatic diagnoses. So far, no long-term diagnostic validity studies were conducted, and a positive diagnostic profile is yet to be identified. We aimed to review the literature on diagnostic signs and symptoms that allow for a discrimination between FCD and neurodegeneration.
METHODS
Systematic review of Ovid-Medline®, Embase and PsycINFO databases. Relevant clinical features were extracted including demographics, symptom history, comorbidities, language and interaction profiles and cognitive assessments. Studies with quantifiable diagnostic accuracy data were included in a diagnostic meta-analysis.
RESULTS
Thirty studies (N = 8602) were included. FCD patients were younger, more educated, and more likely to have a family history of older onset dementia, abrupt symptom onset, and higher rates of anxiety, depression and sleep disturbance. Promising language profiles include longer duration of spoken answer, elaborated examples of memory failures, ability to answer compound and personal questions, and demonstration of working memory during interaction. The pooled analysis of clinical accuracy of different signs revealed that attending alone and bringing a handwritten list of problems particularly increase the odds of a FCD diagnosis. Current evidence from neuropsychometric studies in FCD is scarce.
CONCLUSIONS
Our systematic review reinforces that positive signs contribute for an early differentiation between FCD and neurodegeneration in patients presenting with memory complaints. It is the first to attain quantitative value to clinical observations. These results will inform future diagnostic decision tools and intervention testing.
Topics: Humans; Cognition Disorders; Cognitive Dysfunction; Comorbidity; Language
PubMed: 37567095
DOI: 10.1016/j.jpsychores.2023.111447 -
Emerging Topics in Life Sciences Dec 2023Depression is associated with general sleep disturbance and abnormalities in sleep physiology. For example, compared with control subjects, depressed patients exhibit... (Review)
Review
Depression is associated with general sleep disturbance and abnormalities in sleep physiology. For example, compared with control subjects, depressed patients exhibit lower sleep efficiency, longer rapid eye movement (REM) sleep duration, and diminished slow-wave activity during non-REM sleep. A separate literature indicates that depression is also associated with many distinguishing memory characteristics, including emotional memory bias, overgeneral autobiographical memory, and impaired memory suppression. The sleep and memory features that hallmark depression may both contribute to the onset and maintenance of the disorder. Despite our rapidly growing understanding of the intimate relationship between sleep and memory, our comprehension of how sleep and memory interact in the aetiology of depression remains poor. In this narrative review, we consider how the sleep signatures of depression could contribute to the accompanying memory characteristics.
Topics: Humans; Depression; Emotions; Sleep, REM; Memory, Episodic; Sleep Wake Disorders
PubMed: 38054537
DOI: 10.1042/ETLS20230100 -
Dementia and Neurocognitive Disorders Oct 2023Episodic memory is a system that receives and stores information about temporally dated episodes and their interrelations. Our study aimed to investigate the relevance...
BACKGROUND AND PURPOSE
Episodic memory is a system that receives and stores information about temporally dated episodes and their interrelations. Our study aimed to investigate the relevance of episodic memory to time perception, with a specific focus on simultaneity/order judgment.
METHODS
Experiment 1 employed the simultaneity judgment task to discern differences in time perception between patients with mild cognitive impairment or dementia, and age-matched normals. A mathematical analysis capable of estimating subjects' time processing was utilized to identify the sensory and decisional components of temporal order and simultaneity judgment. Experiment 2 examined how differences in temporal perception relate to performance in temporal order memory, in which time delays play a critical role.
RESULTS
The temporal decision windows for both temporal order and simultaneity judgments exhibited marginal differences between patients with episodic memory impairment, and their healthy counterparts (p = 0.15, t(22) = 1.34). These temporal decision windows may be linked to the temporal separation of events in episodic memory (Pearson's ρ = -0.53, p = 0.05).
CONCLUSIONS
Based on our findings, the frequency of visual events accumulated and encoded in the working memory system in the patients' and normal group appears to be approximately (5.7 and 11.2) Hz, respectively. According to the internal clock model, a lower frequency of event pulses tends to result in underestimation of event duration, which phenomenon might be linked to the observed time distortions in patients with dementia.
PubMed: 38025407
DOI: 10.12779/dnd.2023.22.4.148 -
Brain and Behavior Sep 2023Impairment of episodic memory is largely considered the main cognitive marker of prodromic Alzheimer's disease (AD). Nevertheless, the neuropathological process in AD...
INTRODUCTION
Impairment of episodic memory is largely considered the main cognitive marker of prodromic Alzheimer's disease (AD). Nevertheless, the neuropathological process in AD starts several years before and, apart from biomarkers well defined in the Amyloid (A), Tauopathy (T), Neurodegeneration (N) framework, early clinical and neuropsychological markers able to detect mild cognitive impairment (MCI) due to AD before the appearance of memory disorders are lacking in clinical practice. Investigations on semantic memory have shown promising results in providing an earlier marker of dementia in MCI patients.
METHODS
A total of 253 MCI subjects were followed up every 6 months for 6 years-186 converted to dementia and 67 remained stable at the sixth year of follow-up. Twenty-seven patients progressed in the first 2 years (fast converters), 107 in the third to fourth year (intermediate converters), and 51 after the fourth year of follow-up (slow converters).
RESULTS
Stable MCI subjects performed better than fast decliners in Mini-Mental State Examination (MMSE), several long-term memory scores, and category verbal fluency test (CFT); stable and intermediate converters differ only in MMSE and CFT tests; and stable and slow converters differ only in MMSE and phonological/semantic discrepancy score.
CONCLUSION
Early impairment of semantic memory could predict the evolution to AD before the onset of episodic memory disorders, and the discrepancy between phonological and semantic verbal fluency could be able to detect this impairment in advance in respect of simple CFT tests. The assessment of different aspects of semantic memory and its degradation could represent an early cognitive marker to intercept MCI due to AD in clinical practice.
Topics: Humans; Follow-Up Studies; Disease Progression; Neuropsychological Tests; Cognitive Dysfunction; Alzheimer Disease; Memory Disorders
PubMed: 37550896
DOI: 10.1002/brb3.3098