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Nature Aug 2023Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated...
Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS-STING signalling pathway, which mediates immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt neurodegenerative processes during old age.
Topics: Animals; Humans; Mice; Aging; Brain; Bystander Effect; Cognitive Dysfunction; DNA; Inflammation; Membrane Proteins; Memory Disorders; Microglia; Mitochondria; Neurodegenerative Diseases; Nucleotidyltransferases; Organ Specificity; Signal Transduction; Hippocampus
PubMed: 37532932
DOI: 10.1038/s41586-023-06373-1 -
Journal of Neuroinflammation Nov 2023As one of most common and severe mental disorders, major depressive disorder (MDD) significantly increases the risks of premature death and other medical conditions for... (Review)
Review
As one of most common and severe mental disorders, major depressive disorder (MDD) significantly increases the risks of premature death and other medical conditions for patients. Neuroinflammation is the abnormal immune response in the brain, and its correlation with MDD is receiving increasing attention. Neuroinflammation has been reported to be involved in MDD through distinct neurobiological mechanisms, among which the dysregulation of neurogenesis in the dentate gyrus (DG) of the hippocampus (HPC) is receiving increasing attention. The DG of the hippocampus is one of two niches for neurogenesis in the adult mammalian brain, and neurotrophic factors are fundamental regulators of this neurogenesis process. The reported cell types involved in mediating neuroinflammation include microglia, astrocytes, oligodendrocytes, meningeal leukocytes, and peripheral immune cells which selectively penetrate the blood-brain barrier and infiltrate into inflammatory regions. This review summarizes the functions of the hippocampus affected by neuroinflammation during MDD progression and the corresponding influences on the memory of MDD patients and model animals.
Topics: Adult; Animals; Humans; Depressive Disorder, Major; Depression; Neuroinflammatory Diseases; Hippocampus; Neurogenesis; Mammals
PubMed: 38012702
DOI: 10.1186/s12974-023-02964-x -
The New England Journal of Medicine Feb 2024Cognitive symptoms after coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are well-recognized....
BACKGROUND
Cognitive symptoms after coronavirus disease 2019 (Covid-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are well-recognized. Whether objectively measurable cognitive deficits exist and how long they persist are unclear.
METHODS
We invited 800,000 adults in a study in England to complete an online assessment of cognitive function. We estimated a global cognitive score across eight tasks. We hypothesized that participants with persistent symptoms (lasting ≥12 weeks) after infection onset would have objectively measurable global cognitive deficits and that impairments in executive functioning and memory would be observed in such participants, especially in those who reported recent poor memory or difficulty thinking or concentrating ("brain fog").
RESULTS
Of the 141,583 participants who started the online cognitive assessment, 112,964 completed it. In a multiple regression analysis, participants who had recovered from Covid-19 in whom symptoms had resolved in less than 4 weeks or at least 12 weeks had similar small deficits in global cognition as compared with those in the no-Covid-19 group, who had not been infected with SARS-CoV-2 or had unconfirmed infection (-0.23 SD [95% confidence interval {CI}, -0.33 to -0.13] and -0.24 SD [95% CI, -0.36 to -0.12], respectively); larger deficits as compared with the no-Covid-19 group were seen in participants with unresolved persistent symptoms (-0.42 SD; 95% CI, -0.53 to -0.31). Larger deficits were seen in participants who had SARS-CoV-2 infection during periods in which the original virus or the B.1.1.7 variant was predominant than in those infected with later variants (e.g., -0.17 SD for the B.1.1.7 variant vs. the B.1.1.529 variant; 95% CI, -0.20 to -0.13) and in participants who had been hospitalized than in those who had not been hospitalized (e.g., intensive care unit admission, -0.35 SD; 95% CI, -0.49 to -0.20). Results of the analyses were similar to those of propensity-score-matching analyses. In a comparison of the group that had unresolved persistent symptoms with the no-Covid-19 group, memory, reasoning, and executive function tasks were associated with the largest deficits (-0.33 to -0.20 SD); these tasks correlated weakly with recent symptoms, including poor memory and brain fog. No adverse events were reported.
CONCLUSIONS
Participants with resolved persistent symptoms after Covid-19 had objectively measured cognitive function similar to that in participants with shorter-duration symptoms, although short-duration Covid-19 was still associated with small cognitive deficits after recovery. Longer-term persistence of cognitive deficits and any clinical implications remain uncertain. (Funded by the National Institute for Health and Care Research and others.).
Topics: Adult; Humans; Cognition; Cognitive Dysfunction; COVID-19; Memory Disorders; SARS-CoV-2; Memory; England; Post-Acute COVID-19 Syndrome
PubMed: 38416429
DOI: 10.1056/NEJMoa2311330 -
Bioscience Reports Oct 2023Thiamine (thiamin, B1) is a vitamin necessary for proper cell function. It exists in a free form as a thiamine, or as a mono-, di- or triphosphate. Thiamine plays a...
Thiamine (thiamin, B1) is a vitamin necessary for proper cell function. It exists in a free form as a thiamine, or as a mono-, di- or triphosphate. Thiamine plays a special role in the body as a coenzyme necessary for the metabolism of carbohydrates, fats and proteins. In addition, it participates in the cellular respiration and oxidation of fatty acids: in malnourished people, high doses of glucose result in acute thiamine deficiency. It also participates in energy production in the mitochondria and protein synthesis. In addition, it is also needed to ensure the proper functioning of the central and peripheral nervous system, where it is involved in neurotransmitter synthesis. Its deficiency leads to mitochondrial dysfunction, lactate and pyruvate accumulation, and consequently to focal thalamic degeneration, manifested as Wernicke's encephalopathy or Wernicke-Korsakoff syndrome. It can also lead to severe or even fatal neurologic and cardiovascular complications, including heart failure, neuropathy leading to ataxia and paralysis, confusion, or delirium. The most common risk factor for thiamine deficiency is alcohol abuse. This paper presents current knowledge of the biological functions of thiamine, its antioxidant properties, and the effects of its deficiency in the body.
Topics: Humans; Thiamine; Thiamine Deficiency; Korsakoff Syndrome; Wernicke Encephalopathy; Vitamin B Complex; Malnutrition
PubMed: 37389565
DOI: 10.1042/BSR20230374 -
The Journal of Clinical Investigation Feb 2024Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related...
Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.
Topics: Mice; Animals; Humans; tau Proteins; Resilience, Psychological; Tauopathies; Brain; Alzheimer Disease; Memory Disorders; Neuronal Plasticity; Mice, Transgenic; Kidney; Disease Models, Animal
PubMed: 38299587
DOI: 10.1172/JCI169064 -
General Psychiatry 2023Depression and dementia can lead to generalised cognitive and memory dysfunction. Thus, differentiating these disorders is important and challenging. Pseudodementia is a... (Review)
Review
Depression and dementia can lead to generalised cognitive and memory dysfunction. Thus, differentiating these disorders is important and challenging. Pseudodementia is a term used clinically to describe symptoms that resemble dementia but are caused by other conditions (most frequently depression), rather than being recognised as an official diagnosis. Pseudodementia is characterised by a cognitive impairment that mimics dementia but which does not have its origin in neurological degeneration, deriving instead from functional psychiatric conditions. This condition is more commonly observed in older adults (particularly those over the age of 50 or 60 years), and its risk factors overlap with those for depression. Pseudodementia is essentially characterised by deficits in memory, executive function and speech and, therefore, can easily be confused with dementia, although there are aspects that allow its differentiation. Diagnosing pseudodementia can be difficult, especially as there is significant overlap between its symptoms and those of other conditions. However, it is important to recognise characteristic aspects of this disorder, as its correct identification is essential for proper treatment.
PubMed: 37622032
DOI: 10.1136/gpsych-2022-100939 -
Proceedings of the National Academy of... Sep 2023SYNGAP1 is a Ras-GTPase-activating protein highly enriched at excitatory synapses in the brain. De novo loss-of-function mutations in are a major cause of genetically...
SYNGAP1 is a Ras-GTPase-activating protein highly enriched at excitatory synapses in the brain. De novo loss-of-function mutations in are a major cause of genetically defined neurodevelopmental disorders (NDDs). These mutations are highly penetrant and cause -related intellectual disability (SRID), an NDD characterized by cognitive impairment, social deficits, early-onset seizures, and sleep disturbances. Studies in rodent neurons have shown that Syngap1 regulates developing excitatory synapse structure and function, and heterozygous knockout mice have deficits in synaptic plasticity, learning, and memory and have seizures. However, how specific mutations found in humans lead to disease has not been investigated in vivo. To explore this, we utilized the CRISPR-Cas9 system to generate knock-in mouse models with two distinct known causal variants of SRID: one with a frameshift mutation leading to a premature stop codon, and a second with a single-nucleotide mutation in an intron that creates a cryptic splice acceptor site leading to premature stop codon, . While reduction in mRNA varies from 30 to 50% depending on the specific mutation, both models show ~50% reduction in Syngap1 protein, have deficits in synaptic plasticity, and recapitulate key features of SRID including hyperactivity and impaired working memory. These data suggest that half the amount of SYNGAP1 protein is key to the pathogenesis of SRID. These results provide a resource to study SRID and establish a framework for the development of therapeutic strategies for this disorder.
Topics: Humans; Animals; Mice; Intellectual Disability; Codon, Nonsense; Seizures; Epilepsy; Brain; Disease Models, Animal; Memory Disorders; ras GTPase-Activating Proteins
PubMed: 37669379
DOI: 10.1073/pnas.2308891120