Activation of the Neuronal Cell Cycle in Brains in Amnestic Mild Cognitive Impairment: Early Involvement in the Progression of Alzheimer's Disease.

Activation of cell-cycle machinery in Alzheimer's disease (AD) brain was reported by Mark Smith and colleagues and by other researchers. Among other biochemical processes underlying this activation, the notion that AD brain, under the onslaught of oxidative and nitrosative damage leading to neuronal loss, neurons would attempt to replenish their numbers by entering the cell cycle. However, being post-mitotic, neurons entering the cell cycle would become trapped therein, ultimately leading to death of these neurons. Yang and co-workers and the Butterfield laboratory first reported that similar activation of the cell cycle was present in the brains of individuals with amnestic mild cognitive impairment (MCI), arguably the earliest clinical stage of AD, but who demonstrate normal activities of daily living and no dementia. Activation of the cell cycle in MCI brain is consonant with the concept that this process is an early aspect in the progression of AD. This brief review article discusses these findings and recognizes the contribution of Dr. Mark Smith to the investigation of cell-cycle activation in AD brain and other aspects of AD neuropathology.

Biliverdin Reductase-A integrates insulin signaling with mitochondrial metabolism through phosphorylation of GSK3ß.

Brain insulin resistance links the failure of energy metabolism with cognitive decline in both type 2 Diabetes Mellitus (T2D) and Alzheimer's disease (AD), although the molecular changes preceding overt brain insulin resistance remain unexplored. Abnormal biliverdin reductase-A (BVR-A) levels were observed in both T2D and AD and were associated with insulin resistance. Here, we demonstrate that reduced BVR-A levels alter insulin signaling and mitochondrial bioenergetics in the brain. Loss of BVR-A leads to IRS1 hyper-activation but dysregulates Akt-GSK3ß complex in response to insulin, hindering the accumulation of pGSK3ßS9 into the mitochondria. This event impairs oxidative phosphorylation and fosters the activation of the mitochondrial Unfolded Protein Response (UPRmt). Remarkably, we unveil that BVR-A is required to shuttle pGSK3ßS9 into the mitochondria. Our data sheds light on the intricate interplay between insulin signaling and mitochondrial metabolism in the brain unraveling potential targets for mitigating the development of brain insulin resistance and neurodegeneration.

Protein Oxidation in Aging and Alzheimer's Disease Brain.

Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review, we summarize the role of protein oxidation in normal aging and Alzheimer's disease (AD). The major emphasis of this review article is on the carbonylation and nitration of proteins in AD and mild cognitive impairment (MCI). The oxidatively modified proteins showed a strong correlation with the reported changes in brain structure, carbohydrate metabolism, synaptic transmission, cellular energetics, etc., of both MCI and AD brains compared to the controls. Some proteins were found to be common targets of oxidation and were observed during the early stages of AD, suggesting that those changes might be critical in the onset of symptoms and/or formation of the pathological hallmarks of AD. Further studies are required to fully elucidate the role of protein oxidation and nitration in the progression and pathogenesis of AD.

Observation of Seven Astrophysical Tau Neutrino Candidates with IceCube.

We report on a measurement of astrophysical tau neutrinos with 9.7 yr of IceCube data. Using convolutional neural networks trained on images derived from simulated events, seven candidate ν_{τ} events were found with visible energies ranging from roughly 20 TeV to 1 PeV and a median expected parent ν_{τ} energy of about 200 TeV. Considering backgrounds from astrophysical and atmospheric neutrinos, and muons from π^{±}/K^{±} decays in atmospheric air showers, we obtain a total estimated background of about 0.5 events, dominated by non-ν_{τ} astrophysical neutrinos. Thus, we rule out the absence of astrophysical ν_{τ} at the 5σ level. The measured astrophysical ν_{τ} flux is consistent with expectations based on previously published IceCube astrophysical neutrino flux measurements and neutrino oscillations.

Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease.

Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, and it seems to link different hypotheses and mechanisms of AD neuropathology with high fidelity. The brain is particularly vulnerable to oxidative damage, mainly because of its unique lipid composition, resulting in an amplified cascade of redox reactions that target several cellular components/functions ultimately leading to neurodegeneration. The present review highlights the "OS hypothesis of AD," including amyloid beta-peptide-associated mechanisms, the role of lipid and protein oxidation unraveled by redox proteomics, and the antioxidant strategies that have been investigated to modulate the progression of AD. Collected studies from our groups and others have contributed to unraveling the close relationships between perturbation of redox homeostasis in the brain and AD neuropathology by elucidating redox-regulated events potentially involved in both the pathogenesis and progression of AD. However, the complexity of AD pathological mechanisms requires an in-depth understanding of several major intracellular pathways affecting redox homeostasis and relevant for brain functions. This understanding is crucial to developing pharmacological strategies targeting OS-mediated toxicity that may potentially contribute to slow AD progression as well as improve the quality of life of persons with this severe dementing disorder.

Oxidative Stress in Brain in Amnestic Mild Cognitive Impairment.

Amnestic mild cognitive impairment (MCI), arguably the earliest clinical stage of Alzheimer disease (AD), is characterized by normal activities of daily living but with memory issues but no dementia. Oxidative stress, with consequent damaged key proteins and lipids, are prominent even in this early state of AD. This review article outlines oxidative stress in MCI and how this can account for neuronal loss and potential therapeutic strategies to slow progression to AD.

Cellular Stress Response (Hormesis) in Response to Bioactive Nutraceuticals with Relevance to Alzheimer Disease.

Significance: Alzheimer's disease (AD) is the most common form of dementia associated with aging. As the large Baby Boomer population ages, risk of developing AD increases significantly, and this portion of the population will increase significantly over the next several decades. Recent Advances: Research suggests that a delay in the age of onset by 5 years can dramatically decrease both the incidence and cost of AD. In this review, the role of nuclear factor erythroid 2-related factor 2 (Nrf2) in AD is examined in the context of heme oxygenase-1 (HO-1) and biliverdin reductase-A (BVR-A) and the beneficial potential of selected bioactive nutraceuticals. Critical Issues: Nrf2, a transcription factor that binds to enhancer sequences in antioxidant response elements (ARE) of DNA, is significantly decreased in AD brain. Downstream targets of Nrf2 include, among other proteins, HO-1. BVR-A is activated when biliverdin is produced. Both HO-1 and BVR-A also are oxidatively or nitrosatively modified in AD brain and in its earlier stage, amnestic mild cognitive impairment (MCI), contributing to the oxidative stress, altered insulin signaling, and cellular damage observed in the pathogenesis and progression of AD. Bioactive nutraceuticals exhibit anti-inflammatory, antioxidant, and neuroprotective properties and are potential topics of future clinical research. Specifically, ferulic acid ethyl ester, sulforaphane, epigallocatechin-3-gallate, and resveratrol target Nrf2 and have shown potential to delay the progression of AD in animal models and in some studies involving MCI patients. Future Directions: Understanding the regulation of Nrf2 and its downstream targets can potentially elucidate therapeutic options for delaying the progression of AD. Antioxid. Redox Signal. 38, 643-669.

Long-term trends in particulate matter from wood burning in the United Kingdom: Dependence on weather and social factors.

Particulate matter from wood burning emissions (Cwood) was quantified at five locations in the United Kingdom (UK), comprising three rural and two urban sites between 2009 and 2021. The aethalometer method was used. Mean winter Cwood concentrations ranged from 0.26 µg m-3 (in rural Scotland) to 1.30 µg m-3 (London), which represented on average 4% (in rural environments) and 5% (urban) of PM10 concentrations; and 8% of PM2.5. Concentrations were greatest in the evenings in winter months, with larger evening concentrations in the weekends at the urban sites. Random-forest (RF) machine learning regression models were used to reconstruct Cwood concentrations using both meteorological and temporal explanatory variables at each site. The partial dependency plots indicated that temperature and wind speed were the meteorological variables explaining the greatest variability in Cwood, with larger concentrations during cold and calm conditions. Peaks of Cwood concentrations took place during and after events that are celebrated with bonfires. These were Guy Fawkes events in the urban areas and on New Year's Day at the rural sites; the later probably related to long-range transport. Time series were built using the RF. Having removed weather influences, long-term trends of Cwood were estimated using the Theil Sen method. Trends for 2015-2021 were downward at three of the locations (London, Glasgow and rural Scotland), with rates ranging from -5.5% year-1 to -2.5% year-1. The replacement of old fireplaces with lower emission wood stoves might explain the decrease in Cwood especially at the urban sites The two rural sites in England observed positive trends for the same period but this was not statistically significant.

CAPE and its synthetic derivative VP961 restore BACH1/NRF2 axis in Down Syndrome.

The cells possess several mechanisms to counteract the over-production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), including enzymes such as superoxide dismutase, catalase and glutathione peroxidase. Moreover, an important sensor involved in the anti-oxidant response is KEAP1-NRF2-ARE signaling complex. Under oxidative stress (OS), the transcription factor NRF2 can dissociate from the KEAP1-complex in the cytosol and translocate into the nucleus to promote the transcriptional activation of anti-oxidant genes, such as heme oxygenase 1 and NADPH quinone oxidoreductase. Within this context, the activation of NRF2 response is further regulated by BACH1, a transcription repressor, that compete with the KEAP1-NRF2-ARE complex. In this work, we focused on the role of BACH1/NRF2 ratio in the regulation of the anti-oxidant response, proposing their antithetical relation as a valuable target for a therapeutic strategy to test drugs able to exert neuroprotective effects, notably in aging and neurodegenerative diseases. Among these, Down syndrome (DS) is a complex genetic disorder characterized by BACH1 gene triplication that likely results in the impairment of NRF2 causing increased OS. Our results revealed that BACH1 overexpression alters the BACH1/NRF2 ratio in the nucleus and disturbs the induction of antioxidant response genes ultimately resulting in the accumulation of oxidative damage both in Ts2Cje mice (a mouse model of DS) and human DS lymphoblastoid cell lines (LCLs). Based on this evidence, we tested Caffeic Acid Phenethyl Ester (CAPE) and the synthetic analogue VP961, which have been proven to modulate NRF2 activity. We showed that CAPE and VP961 administration to DS LCLs was able to promote NRF2 nuclear translocation, which resulted in the amelioration of antioxidant response. Overall, our study supports the hypothesis that BACH1 triplication in DS subjects is implicated in the alteration of redox homeostasis and therapeutic strategies to overcome this effect are under investigation in our laboratory.

Extracellular vesicles released after cranial radiation: An insight into an early mechanism of brain injury.

Cranial radiation is important for treating both primary brain tumors and brain metastases. A potential delayed side effect of cranial radiation is neurocognitive function decline. Early detection of CNS injury might prevent further neuronal damage. Extracellular vesicles (EVs) have emerged as a potential diagnostic tool because of their unique membranous characteristics and cargos. We investigated whether EVs can be an early indicator of CNS injury by giving C57BJ/6 mice 10 Gy cranial IR. EVs were isolated from sera to quantify: 1) number of EVs using nanoparticle tracking analysis (NTA); 2) Glial fibrillary acidic protein (GFAP), an astrocyte marker; and 3) protein-bound 4-hydroxy-2-nonenal (HNE) adducts, an oxidative damage marker. Brain tissues were prepared for immunohistochemistry staining and protein immunoblotting. The results demonstrate: 1) increased GFAP levels (p < 0.05) in EVs, but not brain tissue, in the IR group; and 2) increased HNE-bound protein adduction levels (p < 0.05). The results support using EVs as an early indicator of cancer therapy-induced neuronal injury.

Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal-derived extracellular vesicles.

INTRODUCTION: Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing. METHODS: Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways. RESULTS: nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636 , a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3ßSer9 were also found. CONCLUSIONS: The alteration of the insulin-signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population.

Altered Metabolism in Alzheimer Disease Brain: Role of Oxidative Stress.

Significance: Alzheimer disease (AD) is an all-too-common condition in the aging population. However, aging does not automatically equal neurodegeneration and memory decline. Recent Advances: This review article involves metabolic changes in the AD brain that are related to oxidative stress. Selected pathways are identified as potential targets for intervention in AD. Critical Issues: One of the main factors of AD is the oxidative imbalance within the central nervous system, causing a disruption in metabolic processes. Reactive oxygen species (ROS) are a natural consequence of many cellular processes, especially those associated with mitochondria, such as the electron transport chain. Some ROS, when kept under control and maintained at reasonable levels, often play roles in cell signaling. The cellular damage of ROS arises when oxidative imbalance occurs, in which case ROS are not controlled, leading to a myriad of alterations in cellular metabolic processes. These altered pathways include, among others, dysfunctional glycolysis, calcium regulation, lipid metabolism, mitochondrial processes, and mammalian target of rapamycin pathway dysregulation. Future Directions: Understanding how ROS can lead to these alterations can, ideally, elucidate therapeutic options for retarding AD progression in the aging population. Antioxid. Redox Signal. 36, 1289-1305.

Ubiquitin carboxyl-terminal hydrolase L-1 in brain: Focus on its oxidative/nitrosative modification and role in brains of subjects with Alzheimer disease and mild cognitive impairment.

Neurons must remove aggregated, damaged proteins in order to survive. Among the ways of facilitating this protein quality control is the ubiquitin-proteasomal system (UPS). Aggregated, damaged proteins are targeted for destruction by the UPS by acquiring a polymer of ubiquitin residues that serves as a signal for transport to the UPS. However, before this protein degradation can occur, the polyubiquitin chain must be removed, one residue at a time, a reaction facilitated by the enzyme, ubiquitin C-terminal hydrolase (UCH-L1). In Alzheimer disease brain, this normally abundant protein is both of lower levels and oxidatively and nitrosatively modified than in control brain. This causes diminished function of the pleiotropic UCH-L1 enzyme with consequent pathological alterations in AD brain, and the author asserts the oxidative and nitrosative alterations of UCH-L1 are major contributors to mechanisms of neuronal death in this devastating dementing disorder and its earlier stage, mild cognitive impairment (MCI). This review paper outlines these findings in AD and MCI brain.

The interplay among oxidative stress, brain insulin resistance and AMPK dysfunction contribute to neurodegeneration in type 2 diabetes and Alzheimer disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly followed by vascular dementia. In addition to clinically diagnosed dementia, cognitive dysfunction has been reported in diabetic patients. Recent studies are now beginning to recognize type 2 diabetes mellitus (T2DM), characterized by chronic hyperglycemia and insulin resistance, as a risk factor for AD and other cognitive disorders. While studies on insulin action have remained traditionally in the domain of peripheral tissues, the detrimental effects of insulin resistance in the central nervous system on cognitive dysfunction are increasingly being reported in recent clinical and preclinical studies. Brain functions require continuous supply of glucose and oxygen and a tight regulation of metabolic processes. Loss of this metabolic regulation has been proposed to be a contributor to memory dysfunction associated with neurodegeneration. Within the above scenario, this review will focus on the interplay among oxidative stress (OS), insulin resistance and AMPK dysfunctions in the brain by highlighting how these neurotoxic events contribute to neurodegeneration. We provide an overview on the detrimental effects of OS on proteins regulating insulin signaling and how these alterations impact cell metabolic dysfunctions through AMPK dysregulation. Such processes, we assert, are critically involved in the molecular pathways that underlie AD.

Chemotherapy-induced cognitive impairment: focus on the intersection of oxidative stress and TNFα.

Chemotherapy-induced cognitive impairment (CICI) has been observed in a large fraction of cancer survivors. Although many of the chemotherapeutic drugs do not cross the blood-brain barrier, following treatment, the structure and function of the brain are altered and cognitive dysfunction occurs in a significant number of cancer survivors. The means by which CICI occurs is becoming better understood, but there still remain unsolved questions of the mechanisms involved. The hypotheses to explain CICI are numerous. More than 50% of FDA-approved cancer chemotherapy agents are associated with reactive oxygen species (ROS) that lead to oxidative stress and activate a myriad of pathways as well as inhibit pathways necessary for proper brain function. Oxidative stress triggers the activation of different proteins, one in particular is tumor necrosis factor alpha (TNFα). Following treatment with various chemotherapy agents, this pro-inflammatory cytokine binds to its receptors at the blood-brain barrier and translocates to the parenchyma via receptor-mediated endocytosis. Once in brain, TNFα initiates pathways that may eventually lead to neuronal death and ultimately cognitive impairment. TNFα activation of the c-jun N-terminal kinases (JNK) and Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathways may contribute to both memory decline and loss of higher executive functions reported in patients after chemotherapy treatment. Chemotherapy also affects the brain's antioxidant capacity, allowing for accumulation of ROS. This review expands on these topics to provide insights into the possible mechanisms by which the intersection of oxidative stress and TNFΑ are involved in chemotherapy-induced cognitive impairment.

Healthy dietary intake moderates the effects of age on brain iron concentration and working memory performance.

Age-related brain iron accumulation is linked with oxidative stress, neurodegeneration and cognitive decline. Certain nutrients can reduce brain iron concentration in animal models, however, this association is not well established in humans. Moreover, it remains unknown if nutrition can moderate the effects of age on brain iron concentration and/or cognition. Here, we explored these issues in a sample of 73 healthy older adults (61-86 years old), while controlling for several factors such as age, gender, years of education, physical fitness and alcohol-intake. Quantitative susceptibility mapping was used for assessment of brain iron concentration and participants performed an N-Back paradigm to evaluate working memory performance. Nutritional-intake was assessed via a validated questionnaire. Nutrients were grouped into nutrition factors based on previous literature and factor analysis. One factor, comprised of vitamin E, lysine, DHA omega-3 and LA omega-6 PUFA, representing food groups such as nuts, healthy oils and fish, moderated the effects of age on both brain iron concentration and working memory performance, suggesting that these nutrients may slow the rate of brain iron accumulation and working memory declines in aging.

Onset of Senescence and Steatosis in Hepatocytes as a Consequence of a Shift in the Diacylglycerol/Ceramide Balance at the Plasma Membrane.

Ceramide and diacylglycerol (DAG) are bioactive lipids and mediate many cellular signaling pathways. Sphingomyelin synthase (SMS) is the single metabolic link between the two, while SMS2 is the only SMS form located at the plasma membrane. SMS2 functions were investigated in HepG2 cell lines stably expressing SMS2. SMS2 overexpression did not alter sphingomyelin (SM), phosphatidylcholine (PC), or ceramide levels. DAG content increased by approx. 40% and led to downregulation of DAG-dependent protein kinase C (PKC). SMS2 overexpression also induced senescence, characterized by positivity for ß-galactosidase activity and heterochromatin foci. HepG2-SMS2 cells exhibited protruded mitochondria and suppressed mitochondrial respiration rates. ATP production and the abundance of Complex V were substantially lower in HepG2-SMS2 cells as compared to controls. SMS2 overexpression was associated with inflammasome activation based on increases in IL-1ß and nlpr3 mRNA levels. HepG2-SMS2 cells exhibited lipid droplet accumulation, constitutive activation of AMPK based on elevated 172Thr phosphorylation, increased AMPK abundance, and insensitivity to insulin suppression of AMPK. Thus, our results show that SMS2 regulates DAG homeostasis and signaling in hepatocytes and also provide proof of principle for the concept that offset in bioactive lipids' production at the plasma membrane can drive the senescence program in association with steatosis and, seemingly, by cell-autonomous mechanisms.

The preparation temperature influences the physicochemical nature and activity of nanoceria.

Cerium oxide nanoparticles, so-called nanoceria, are engineered nanomaterials prepared by many methods that result in products with varying physicochemical properties and applications. Those used industrially are often calcined, an example is NM-212. Other nanoceria have beneficial pharmaceutical properties and are often prepared by solvothermal synthesis. Solvothermally synthesized nanoceria dissolve in acidic environments, accelerated by carboxylic acids. NM-212 dissolution has been reported to be minimal. To gain insight into the role of high-temperature exposure on nanoceria dissolution, product susceptibility to carboxylic acid-accelerated dissolution, and its effect on biological and catalytic properties of nanoceria, the dissolution of NM-212, a solvothermally synthesized nanoceria material, and a calcined form of the solvothermally synthesized nanoceria material (ca. 40, 4, and 40 nm diameter, respectively) was investigated. Two dissolution methods were employed. Dissolution of NM-212 and the calcined nanoceria was much slower than that of the non-calcined form. The decreased solubility was attributed to an increased amount of surface Ce4+ species induced by the high temperature. Carboxylic acids doubled the very low dissolution rate of NM-212. Nanoceria dissolution releases Ce3+ ions, which, with phosphate, form insoluble cerium phosphate in vivo. The addition of immobilized phosphates did not accelerate nanoceria dissolution, suggesting that the Ce3+ ion release during nanoceria dissolution was phosphate-independent. Smaller particles resulting from partial nanoceria dissolution led to less cellular protein carbonyl formation, attributed to an increased amount of surface Ce3+ species. Surface reactivity was greater for the solvothermally synthesized nanoceria, which had more Ce3+ species at the surface. The results show that temperature treatment of nanoceria can produce significant differences in solubility and surface cerium valence, which affect the biological and catalytic properties of nanoceria.

mTOR in Alzheimer disease and its earlier stages: Links to oxidative damage in the progression of this dementing disorder.

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population and has worldwide impact. The etiology of the disease is complex and results from the confluence of multiple mechanisms ultimately leading to neuronal loss and cognitive decline. Among risk factors, aging is the most relevant and accounts for several pathogenic events that contribute to disease-specific toxic mechanisms. Accumulating evidence linked the alterations of the mammalian target of rapamycin (mTOR), a serine/threonine protein kinase playing a key role in the regulation of protein synthesis and degradation, to age-dependent cognitive decline and pathogenesis of AD. To date, growing studies demonstrated that aberrant mTOR signaling in the brain affects several pathways involved in energy metabolism, cell growth, mitochondrial function and proteostasis. Recent advances associated alterations of the mTOR pathway with the increased oxidative stress. Disruption of all these events strongly contribute to age-related cognitive decline including AD. The current review discusses the main regulatory roles of mTOR signaling network in the brain, focusing on its role in autophagy, oxidative stress and energy metabolism. Collectively, experimental data suggest that targeting mTOR in the CNS can be a valuable strategy to prevent/slow the progression of AD.