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Kynurenic acid inflammatory signaling expands in primates and impairs prefrontal cortical cognition.BioRxiv : the Preprint Server For... Jun 2024Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's...
Cognitive deficits from dorsolateral prefrontal cortex (dlPFC) dysfunction are common in neuroinflammatory disorders, including long-COVID, schizophrenia and Alzheimer's disease, and have been correlated with kynurenine inflammatory signaling. Kynurenine is further metabolized to kynurenic acid (KYNA) in brain, where it blocks NMDA and α7-nicotinic receptors (nic-α7Rs). These receptors are essential for neurotransmission in dlPFC, suggesting that KYNA may cause higher cognitive deficits in these disorders. The current study found that KYNA and its synthetic enzyme, KAT II, have greatly expanded expression in primate dlPFC in both glia and neurons. Local application of KYNA onto dlPFC neurons markedly reduced the delay-related firing needed for working memory via actions at NMDA and nic-α7Rs, while inhibition of KAT II enhanced neuronal firing in aged macaques. Systemic administration of agents that reduce KYNA production similarly improved cognitive performance in aged monkeys, suggesting a therapeutic avenue for the treatment of cognitive deficits in neuroinflammatory disorders.
PubMed: 38915595
DOI: 10.1101/2024.06.13.598842 -
Frontiers in Aging Neuroscience 2024Olfactory dysfunction was associated with poorer cognition. However, the association between transient receptor potential cation channel subfamily A member 1 (TRPA1) and...
BACKGROUND
Olfactory dysfunction was associated with poorer cognition. However, the association between transient receptor potential cation channel subfamily A member 1 (TRPA1) and cognitive function have not been studied. This study aimed to evaluate the mediation effect of TRPA1 on the association between olfactory and cognitive function among Chinese older adults.
METHODS
We recruited 121 participants with cognitive impairment (CI) and 135 participants with normal cognition (NC) from a memory clinic and the "Shanghai Aging Study." Olfactory identification of each participant was measured by the Sniffin' Sticks Screening Test 12 (SSST-12). Serum TRPA1 were quantified using the Enzyme-Linked Immunosorbent Assay. The mediation effects of TRPA1 on the association between olfactory function and cognitive function were explored using mediation analysis.
RESULTS
The CI group had a significantly higher proportion of the high level of serum TRPA1 (58.7%) than the NC group (42.2%) ( = 0.0086). After adjusted for gender, age, and years of education, mediation analysis verified that TRPA1 partially mediated the association between SSST-12 and Mini Mental State Examination (MMSE). It also verified that TRPA1 partially mediated the association between the identification of peppermint and MMSE.
CONCLUSION
Our study emphasizes the mediation role of TRPA1 in the relationship between olfactory and cognitive function among older adults. Further research is necessary to explore the mechanism of TRPA1 on the relationship between olfactory and cognitive decline.
PubMed: 38915349
DOI: 10.3389/fnagi.2024.1411031 -
BMC Psychology Jun 2024Video games have become a prevalent source of entertainment, especially among children. Furthermore, the amount of time spent playing video games has grown dramatically....
BACKGROUND
Video games have become a prevalent source of entertainment, especially among children. Furthermore, the amount of time spent playing video games has grown dramatically. The purpose of this research was to examine the mediation effects of attention and child memory on the relationship between video games addiction and cognitive and learning abilities in Egyptian children.
METHODS
A cross-sectional research design was used in the current study in two schools affiliated with Dakahlia District, Egypt. The study included 169 children aged 9 to 13 who met the inclusion criteria, and their mothers provided the questionnaire responses. The data collection methods were performed over approximately four months from February to May. Data were collected using different tools: Socio-demographic Interview, Game Addiction Scale for Children (GASC), Children's Memory Questionnaire (CMQ), Clinical Attention Problems Scale, Learning, Executive, and Attention Functioning (LEAF) Scale.
RESULTS
There was a significant indirect effect of video game addiction on cognitive and learning skills through attention, but not child memory. Video game addiction has a significant impact on children's attention and memory. Both attention and memory have a significant impact on a child's cognitive and learning skills.
CONCLUSIONS
These results revealed the significant effect of video game addiction on cognitive and learning abilities in the presence of mediators. It also suggested that attention-focused therapies might play an important role in minimizing the harmful effects of video game addiction on cognitive and learning abilities.
Topics: Humans; Child; Female; Male; Attention; Video Games; Adolescent; Cross-Sectional Studies; Memory; Learning; Cognition; Behavior, Addictive; Egypt; Internet Addiction Disorder; Executive Function
PubMed: 38915089
DOI: 10.1186/s40359-024-01849-9 -
PloS One 2024The cannabinoid receptor type 1 (CB1R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder...
Cannabinoid receptor 1 positive allosteric modulator ZCZ011 shows differential effects on behavior and the endocannabinoid system in HIV-1 Tat transgenic female and male mice.
The cannabinoid receptor type 1 (CB1R) is a promising therapeutic target for various neurodegenerative diseases, including HIV-1-associated neurocognitive disorder (HAND). However, the therapeutic potential of CB1R by direct activation is limited due to its psychoactive side effects. Therefore, research has focused on indirectly activating the CB1R by utilizing positive allosteric modulators (PAMs). Studies have shown that CB1R PAMs (ZCZ011 and GAT211) are effective in mouse models of Huntington's disease and neuropathic pain, and hence, we assess the therapeutic potential of ZCZ011 in a well-established mouse model of neuroHIV. The current study investigates the effect of chronic ZCZ011 treatment (14 days) on various behavioral paradigms and the endocannabinoid system in HIV-1 Tat transgenic female and male mice. Chronic ZCZ011 treatment (10 mg/kg) did not alter body mass, locomotor activity, or anxiety-like behavior regardless of sex or genotype. However, differential effects were noted in hot plate latency, motor coordination, and recognition memory in female mice only, with ZCZ011 treatment increasing hot plate latency and improving motor coordination and recognition memory. Only minor effects or no alterations were seen in the endocannabinoid system and related lipids except in the cerebellum, where the effect of ZCZ011 was more pronounced in female mice. Moreover, AEA and PEA levels in the cerebellum were positively correlated with improved motor coordination in female mice. In summary, these findings indicate that chronic ZCZ011 treatment has differential effects on antinociception, motor coordination, and memory, based on sex and HIV-1 Tat expression, making CB1R PAMs potential treatment options for HAND without the psychoactive side effects.
Topics: Animals; Female; Male; Mice, Transgenic; Endocannabinoids; Receptor, Cannabinoid, CB1; Mice; tat Gene Products, Human Immunodeficiency Virus; HIV-1; Allosteric Regulation; Behavior, Animal; Motor Activity; Disease Models, Animal
PubMed: 38913661
DOI: 10.1371/journal.pone.0305868 -
ELife Jun 2024Downregulating emotional overreactions toward threats is fundamental for developing treatments for anxiety and post-traumatic disorders. The prefrontal cortex (PFC) is...
Downregulating emotional overreactions toward threats is fundamental for developing treatments for anxiety and post-traumatic disorders. The prefrontal cortex (PFC) is critical for top-down modulatory processes, and despite previous studies adopting repetitive transcranial magnetic stimulation (rTMS) over this region provided encouraging results in enhancing extinction, no studies have hitherto explored the effects of stimulating the medial anterior PFC (aPFC, encompassing the Brodmann area 10) on threat memory and generalization. Here we showed that rTMS over the aPFC applied before threat memory retrieval immediately decreases implicit reactions to learned and novel stimuli in humans. These effects enduringly persisted 1 week later in the absence of rTMS. No effects were detected on explicit recognition. Critically, rTMS over the aPFC resulted in a more pronounced reduction of defensive responses compared to rTMS targeting the dorsolateral PFC. These findings reveal a previously unexplored prefrontal region, the modulation of which can efficiently and durably inhibit implicit reactions to learned threats. This represents a significant advancement toward the long-term deactivation of exaggerated responses to threats.
Topics: Humans; Fear; Prefrontal Cortex; Transcranial Magnetic Stimulation; Male; Young Adult; Female; Adult; Extinction, Psychological
PubMed: 38913410
DOI: 10.7554/eLife.85951 -
Biology Open Jun 2024Changes in mitochondrial distribution are a feature of numerous age-related neurodegenerative diseases. In Drosophila, reducing the activity of Cdk5 causes a...
Changes in mitochondrial distribution are a feature of numerous age-related neurodegenerative diseases. In Drosophila, reducing the activity of Cdk5 causes a neurodegenerative phenotype and is known to affect several mitochondrial properties. Therefore, we investigated whether alterations of mitochondrial distribution are involved in Cdk5-associated neurodegeneration. We find that reducing Cdk5 activity does not alter the balance of mitochondrial localization to the somatodendritic vs. axonal neuronal compartments of the mushroom body, the learning and memory center of the Drosophila brain. We do, however, observe changes in mitochondrial distribution at the axon initial segment (AIS), a neuronal compartment located in the proximal axon involved in neuronal polarization and action potential initiation. Specifically, we observe that mitochondria are partially excluded from the AIS in wild-type neurons, but that this exclusion is lost upon reduction of Cdk5 activity, concomitant with the shrinkage of the AIS domain that is known to occur in this condition. This mitochondrial redistribution into the AIS is not likely due to the shortening of the AIS domain itself but rather due to altered Cdk5 activity. Furthermore, mitochondrial redistribution into the AIS is unlikely to be an early driver of neurodegeneration in the context of reduced Cdk5 activity.
PubMed: 38912559
DOI: 10.1242/bio.060335 -
Alzheimer's & Dementia (Amsterdam,... 2024Vascular pathology is known to contribute to dementia and vascular endothelial growth factor (VEGF) is a well-established biomarker associated with vascular alterations....
INTRODUCTION
Vascular pathology is known to contribute to dementia and vascular endothelial growth factor (VEGF) is a well-established biomarker associated with vascular alterations. Nonetheless, research findings on VEGF in Alzheimer's disease (AD) and vascular dementia (VaD) are inconsistent across various studies.
METHODS
We conducted a meta-analysis to elucidate relationships between VEGF and AD/VaD.
RESULTS
Twenty-four studies were included. Pooled data showed that both blood and cerebrospinal fluid (CSF) VEGF levels were higher in VaD patients, whereas no significant difference was found between AD patients and healthy controls. However, the correlation between blood VEGF and AD was found among studies with AD pathology verification. And blood VEGF levels were higher in AD patients than controls in "age difference < 5 years" subgroup and CSF samples for European cohorts.
DISCUSSION
This study highlights that VEGF is more effective for the diagnosis of VaD and vascular factors are also an important contributor in AD.
HIGHLIGHTS
Vascular endothelial growth factor (VEGF) levels were higher in the vascular dementia group, but not in the overall Alzheimer's disease (AD) group.Correlation between VEGF and AD was found among studies with clear AD pathological verification.Elevated VEGF in the cerebrospinal fluid might be a diagnostic marker for AD in European populations.
PubMed: 38912304
DOI: 10.1002/dad2.12612 -
Journal of Inflammation Research 2024Alzheimer's disease (AD) is the most common neurodegenerative illness, characterized by memory loss and cognitive decline, accounting for 60-80% of dementia cases. AD is... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative illness, characterized by memory loss and cognitive decline, accounting for 60-80% of dementia cases. AD is characterized by senile plaques made up of amyloid β (Aβ) protein, intracellular neurofibrillary tangles caused by hyperphosphorylation of tau protein linked with microtubules, and neuronal loss. Currently, therapeutic treatments and nanotechnological developments are effective in treating the symptoms of AD, but a cure for the illness has not yet been found. Recently, the increased study of extracellular vesicles (EVs) has led to a growing awareness of their significant involvement in neurodegenerative disorders, including AD. Exosomes are small extracellular vesicles that transport various components including messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive compounds from one cell to another, facilitating information transmission and material movement. There is growing evidence indicating that exosomes have complex functions in AD. Exosomes may have a dual role in Alzheimer's disease by contributing to neuronal death and also helping to alleviate the pathological progression of the disease. Therefore, the primary aim of this review is to outline the updated understandings on exosomes biogenesis and many functions of exosomes in the generation, conveyance, distribution, and elimination of hazardous proteins related to Alzheimer's disease. This review is intended to provide novel insights for understanding the development, specific treatment, and early detection of Alzheimer's disease.
PubMed: 38911990
DOI: 10.2147/JIR.S466821 -
Frontiers in Psychiatry 2024Accompanied by a rapid and effective antidepressant effect, electroconvulsive shock (ECS) can also induce learning and memory impairment. Our previous research reported...
Alteration of hyperpolarization-activated cation current-mediated metaplasticity contributes to electroconvulsive shock-induced learning and memory impairment in depressed rats.
BACKGROUND
Accompanied by a rapid and effective antidepressant effect, electroconvulsive shock (ECS) can also induce learning and memory impairment. Our previous research reported that metaplasticity is involved in this process. However, the mechanisms still remain unclear. This study investigated the role of current in the metaplastic changes and learning and memory impairment induced by ECS in depressive rats.
METHODS
Depressive rats received ECS after modelling using chronic unpredictable. ZD7288, a type of current inhibitor was used to verify the effect of current. The sucrose preference test and Morris water maze were used for behavior testing. Changes in metaplasticity was assessed with the LTD/LTP threshold by stimulation at different frequencies. Spontaneous and evoked action potentials (APs) were measured to confirm difference of neuronal excitability. Additionally, the amplitude of current was analyzed.
RESULTS
ECS exerts antidepressant effect, but also induce spatial learning and memory dysfunction. ECS up-regulates the LTD/LTP threshold. In rats treated with ECS, the frequency of spontaneous and evoked APs is significantly reduced. In addition, ECS induces changes in the intrinsic properties of AP, including a decrease of AP-half width and peak amplitude, and an increase in AP time to peak and post-hyperpolarization potential amplitude. In particular, ECS increases both instantaneous and steady-state currents. However, Inhibition of current with ZD7288 results in a relief of learning and memory impairment and a decrease in threshold, as well as a significant reversal of whole-cell electrophysiological changes.
CONCLUSION
ECS-induced learning and memory impairment is caused by neuronal hypoexcitability mediated metaplasticity, and upregulation of LTD/LTP threshold by an increase in current.
PubMed: 38911706
DOI: 10.3389/fpsyt.2024.1365119 -
Journal of Alzheimer's Disease Reports 2024Despite intense investigations, no effective treatment is yet available to reduce plaques and protect memory and learning in patients with Alzheimer's disease (AD), the...
Identification of Cinnamein, a Component of Balsam of Tolu/Peru, as a New Ligand of PPARα for Plaque Reduction and Memory Protection in a Mouse Model of Alzheimer's Disease.
BACKGROUND
Despite intense investigations, no effective treatment is yet available to reduce plaques and protect memory and learning in patients with Alzheimer's disease (AD), the most common neurodegenerative disorder. Therefore, it is important to identify a non-toxic, but effective, treatment option for AD.
OBJECTIVE
Cinnamein, a nontoxic compound, is naturally available in Balsam of Peru and Tolu Balsam. We examined whether cinnamein treatment could decrease plaques and improve cognitive functions in mouse model of AD.
METHODS
We employed analysis, time-resolved fluorescence energy transfer assay, thermal shift assay, primary neuron isolation, western blot, immunostaining, immunohistochemistry, Barnes maze, T maze, and open field behavior.
RESULTS
Oral administration of cinnamein led to significant reduction in amyloid-β plaque deposits in the brain and protection of spatial learning and memory in mice. Peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor, is involved in plaque lowering and increase in hippocampal plasticity. While investigating underlying mechanisms, we found that cinnamein served as a ligand of PPARα. Accordingly, oral cinnamein upregulated the level of PPARα, but not PPARβ, in the hippocampus, and remained unable to decrease plaques from the hippocampus and improve memory and learning in mice lacking PPARα. While A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is one of the drivers of nonamyloidogenic pathway, transcription factor EB (TFEB) is considered as the master regulator of autophagy. Cinnamein treatment was found to upregulate both ADAM10 and TFEB in the brain of mice via PPARα.
CONCLUSIONS
Our results suggest that this balsam component may have therapeutic importance in AD.
PubMed: 38910936
DOI: 10.3233/ADR-230179