Blanchette Rockefeller Neurosciences Institute

Circadian rhythms are internal manifestations of the solar day that permit adaptations to predictable environmental temporal changes. These ~24-h rhythms are controlled by molecular clockworks within the brain that are reset daily to precisely 24 h by exposure to the light-dark cycle. Information from the master clock in the mammalian hypothalamus conveys temporal information to the entire body via humoral and neural communication. A bidirectional relationship exists between mood disorders and circadian rhythms. Mood disorders are often associated with disrupted circadian clock-controlled responses, such as sleep and cortisol secretion, whereas disruption of circadian rhythms via jet lag, night-shift work, or exposure to artificial light at night, can precipitate or exacerbate affective symptoms in susceptible individuals. Evidence suggests strong associations between circadian rhythms and mental health, but only recently have studies begun to discover the direct interactions between the circadian system and mood regulation. This review provides an overview of disrupted circadian rhythms and the relationship to behavioral health and psychiatry. The focus of this review is delineating the role of disruption of circadian rhythms on mood disorders using human night shift studies, as well as jet lag studies to identify links. We also review animal models of disrupted circadian rhythms on affective responses. Lastly, we propose low-cost behavioral and lifestyle changes to improve circadian rhythms and presumably behavioral health.

Recent studies have indicated an association between Alzheimer's disease (AD) and central nervous system (CNS) insulin resistance. However, the cellular mechanisms underlying the link between these two pathologies have not been elucidated. Here we show that signal transduction by neuronal insulin receptors (IR) is strikingly sensitive to disruption by soluble Abeta oligomers (also known as ADDLs). ADDLs are known to accumulate in AD brain and have recently been implicated as primary candidates for initiating deterioration of synapse function, composition, and structure. Using mature cultures of hippocampal neurons, a preferred model for studies of synaptic cell biology, we found that ADDLs caused a rapid and substantial loss of neuronal surface IRs specifically on dendrites bound by ADDLs. Removal of dendritic IRs was associated with increased receptor immunoreactivity in the cell body, indicating redistribution of the receptors. The neuronal response to insulin, measured by evoked IR tyrosine autophosphorylation, was greatly inhibited by ADDLs. Inhibition also was seen with added glutamate or potassium-induced depolarization. The effects on IR function were completely blocked by NMDA receptor antagonists, tetrodotoxin, and calcium chelator BAPTA-AM. Downstream from the IR, ADDLs induced a phosphorylation of Akt at serine473, a modification associated with neurodegenerative and insulin resistance diseases. These results identify novel factors that affect neuronal IR signaling and suggest that insulin resistance in AD brain is a response to ADDLs, which disrupt insulin signaling and may cause a brain-specific form of diabetes as part of an overall pathogenic impact on CNS synapses.

Despite the crucial role played by cholesterol and copper in nutrition and normal brain function, recent evidence indicates that they may both be important factors in the etiology of Alzheimer's disease (AD). Here we provide critical evidence for the role of cholesterol and copper in AD by showing that the addition of trace amounts of copper (0.12 ppm) to water given to cholesterol-fed rabbits can induce beta-amyloid (Abeta) accumulation, including senile plaque-like structures in the hippocampus and temporal lobe, and can significantly retard the ability of rabbits to learn a difficult trace conditioning task. The Abeta deposits do not affect the ability of rabbits to detect or respond to the training stimuli nor to learn a simpler delay conditioning task. Trace amounts of copper in drinking water may influence clearance of Abeta from the brain at the level of the interface between the blood and cerebrovasculature and combined with high cholesterol may be a key component to the accumulation of Abeta in the brain, having a significant impact on learning and memory. Cholesterol-fed rabbits have at least 12 pathological markers seen in AD, suggesting that the cholesterol-fed rabbit is a good animal model for studying AD.

The blood-brain barrier (BBB) presents a significant challenge for treating brain disorders. The hippocampus is a key target for novel therapeutics, playing an important role in Alzheimer's disease (AD), epilepsy, and depression. Preclinical studies have shown that magnetic resonance (MR)-guided low-intensity focused ultrasound (FUS) can reversibly open the BBB and facilitate delivery of targeted brain therapeutics. We report initial clinical trial results evaluating the safety, feasibility, and reversibility of BBB opening with FUS treatment of the hippocampus and entorhinal cortex (EC) in patients with early AD. Six subjects tolerated a total of 17 FUS treatments with no adverse events and neither cognitive nor neurological worsening. Post-FUS contrast MRI revealed immediate and sizable hippocampal parenchymal enhancement indicating BBB opening, followed by BBB closure within 24 h. The average opening was 95% of the targeted FUS volume, which corresponds to 29% of the overall hippocampus volume. We demonstrate that FUS can safely, noninvasively, transiently, reproducibly, and focally mediate BBB opening in the hippocampus/EC in humans. This provides a unique translational opportunity to investigate therapeutic delivery in AD and other conditions.

Alzheimer's disease (AD) characteristically presents with early memory loss. Regulation of K(+) channels, calcium homeostasis, and protein kinase C (PKC) activation are molecular events that have been implicated during associative memory which are also altered or defective in AD. PKC is also involved in the processing of the amyloid precursor protein (APP), a central element in AD pathophysiology. In previous studies, we demonstrated that benzolactam (BL), a novel PKC activator, reversed K(+) channels defects and enhanced secretion of APP alpha in AD cells. In this study we present data showing that another PKC activator, bryostatin 1, at subnanomolar concentrations dramatically enhances the secretion of the alpha-secretase product sAPP alpha in fibroblasts from AD patients. We also show that BL significantly increased the amount of sAPP alpha and reduced A beta 40 in the brains of APP[V717I] transgenic mice. In a more recently developed AD double-transgenic mouse, bryostatin was effective in reducing both brain A beta 40 and A beta 42. In addition, bryostatin ameliorated the rate of premature death and improved behavioral outcomes. Collectively, these data corroborate PKC and its activation as a potentially important means of ameliorating AD pathophysiology and perhaps cognitive impairment, thus offering a promising target for drug development. Because bryostatin 1 is devoid of tumor-promoting activity and is undergoing numerous clinical studies for cancer treatment in humans, it might be readily tested in patients as a potential therapeutic agent for Alzheimer's disease.

Persistent endoplasmic reticulum (ER) stress is thought to drive the pathology of many chronic disorders due to its potential to elicit aberrant inflammatory signaling and facilitate cell death. In neurodegenerative diseases, the accumulation of misfolded proteins and concomitant induction of ER stress in neurons contributes to neuronal dysfunction. In addition, ER stress responses induced in the surrounding neuroglia may promote disease progression by coordinating damaging inflammatory responses, which help fuel a neurotoxic milieu. Nevertheless, there still remains a gap in knowledge regarding the cell-specific mechanisms by which ER stress mediates neuroinflammation. In this review, we will discuss recently uncovered inflammatory pathways linked to the ER stress response. Moreover, we will summarize the present literature delineating how ER stress is generated in Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Multiple Sclerosis, and highlight how ER stress and neuroinflammation intersect mechanistically within the central nervous system. The mechanisms by which stress-induced inflammation contributes to the pathogenesis and progression of neurodegenerative diseases remain poorly understood. Further examination of this interplay could present unappreciated insights into the development of neurodegenerative diseases, and reveal new therapeutic targets.

We measured persistent Na(+) current and membrane properties of bursting-pacemaker and nonbursting inspiratory neurons of the neonatal rat pre-Bötzinger complex (pre-BötC) in brain stem slice preparations with a rhythmically active respiratory network in vitro. In whole-cell recordings, slow voltage ramps (</=100 mV/s) inactivated the fast, spike-generating Na(+) current and yielded N-shaped current-voltage relationships with nonmonotonic, negative-slope regions between -60 and -35 mV when the voltage-sensitive component was isolated. The underlying current was a TTX-sensitive persistent Na(+) current (I(NaP)) since the inward current was present at slow voltage ramp speeds (3.3-100 mV/s) and the current was blocked by 1 microM TTX. We measured the biophysical properties of I(NaP) after subtracting the voltage-insensitive "leak" current (I(Leak)) in the presence of Cd(2+) and in some cases tetraethylammonium (TEA). Peak I(NaP) ranged from -50 to -200 pA at a membrane potential of -30 mV. Decreasing the speed of the voltage ramp caused time-dependent I(NaP) inactivation, but this current was present at ramp speeds as low as 3.3 mV/s. I(NaP) activated at -60 mV and obtained half-maximal activation near -40 mV. The subthreshold voltage dependence and slow inactivation kinetics of I(NaP), which closely resemble those of I(NaP) mathematically modeled as a burst-generation mechanism in pacemaker neurons of the pre-BötC, suggest that I(NaP) predominantly influences bursting dynamics of pre-BötC inspiratory pacemaker neurons in vitro. We also found that the ratio of persistent Na(+) conductance to leak conductance (g(NaP)/g(Leak)) can distinguish the phenotypic subpopulations of bursting pacemaker and nonbursting inspiratory neurons: pacemaker neurons showed g(NaP)/g(Leak) > g(NaP)/g(Leak) in nonpacemaker cells (P < 0.0002). We conclude that I(NaP) is ubiquitously expressed by pre-BötC inspiratory neurons and that bursting pacemaker behavior within the heterogeneous population of inspiratory neurons is achieved with specific ratios of these two conductances, g(NaP) and g(Leak).

Among the pathologic hallmarks of Alzheimer's disease (AD) neurodegeneration, only synaptic loss in the brains of AD patients closely correlates with the degree of dementia in vivo. Here, we describe a molecular basis for this AD loss of synapses: pathological reduction of synaptogenic PKC isozymes and their downstream synaptogenic substrates, such as brain-derived neurotrophic factor. This reduction, particularly of PKC α and ε, occurs in association with elevation of soluble β amyloid protein (Aβ), but before the appearance of the amyloid plaques or neuronal loss in the Tg2576 AD transgenic mouse strain. Conversely, treatment of the Tg2576 mouse brain with the PKC activator, bryostatin-1, restores normal or supranormal levels of PKC α and ε, reduces the level of soluble Aβ, prevents and/or reverses the loss of hippocampal synapses, and prevents the memory impairment observed at 5 months postpartum. Similarly, the PKC ε-specific activator, DCP-LA, effectively prevents synaptic loss, amyloid plaques, and cognitive deficits (also prevented by bryostatin-1) in the much more rapidly progressing 5XFAD transgenic strain. These results suggest that synaptic loss and the resulting cognitive deficits depend on the balance between the lowering effects of Aβ on PKC α and ε versus the lowering effects of PKC on Aβ in AD transgenic mice.

Evidence has shown that the insulin and insulin receptor (IR) play a role in cognitive function. However, the detailed mechanisms underlying insulin's action on learning and memory are not yet understood. Here we investigated changes in long-term memory-associated expression of the IR and downstream molecules in the rat hippocampus. After long-term memory consolidation following a water maze learning experience, gene expression of IR showed an up-regulation in the CA1, but a down-regulation in the CA3 region. These were correlated with a significant reduction in hippocampal IR protein levels. Learning-specific increases in levels of downstream molecules such as IRS-1 and Akt were detected in the synaptic membrane accompanied by decreases in Akt phosphorylation. Translocation of Shc protein to the synaptic membrane and activation of Erk1/2 were also observed after long-term memory formation. Despite the clear memory-correlated alterations in IR signaling pathways, insulin deficits in experimental diabetes mellitus (DM) rats induced by intraperitoneal injections of streptozotocin resulted in only minor memory impairments. This may be due to higher glucose levels in the DM brain, and to compensatory mechanisms from other signaling pathways such as the insulin-like growth factor-1 receptor (IGF-1R) system. Our results suggest that insulin/IR signaling plays a modulatory role in learning and memory processing, which may be compensated for by alternative pathways in the brain when an insulin deficit occurs.

BACKGROUND: Patients receiving standard treatment for chronic subdural hematoma have a high risk of treatment failure. The effect of adjunctive middle meningeal artery embolization on the risk of treatment failure in this population remains unknown. METHODS: We randomly assigned patients with symptomatic chronic subdural hematoma to undergo middle meningeal artery embolization as an adjunct to standard treatment (embolization group) or to receive standard treatment alone (control group). Either surgical or nonsurgical standard treatment had been chosen for each patient before randomization. The primary efficacy outcome was a composite of the following events: recurrent or residual chronic subdural hematoma (measuring >10 mm) at 180 days; reoperation or surgical rescue within 180 days; or major disabling stroke, myocardial infarction, or death from neurologic causes within 180 days. The primary safety outcome was a composite of major disabling stroke or death from any cause within 30 days. RESULTS: Among 310 enrolled patients, 149 were randomly assigned to the embolization group and 161 to the control group; 189 patients were to receive surgical standard treatment and 121 nonsurgical standard treatment. The mean age of the patients was 73 years, and 70% were men. In the primary efficacy analysis, a primary-outcome event occurred in 19 of 120 patients (16%) in the embolization group, as compared with 47 of 129 patients (36%) in the control group (odds ratio, 0.36; 95% confidence interval, 0.20 to 0.66; P = 0.001). In the primary safety analysis, 4 of 144 patients (3%) in the embolization group and 5 of 166 patients (3%) in the control group either had a major disabling stroke or died within 30 days. Through 180 days, 12 patients (8%) in the embolization group and 9 patients (5%) in the control group had died, with death from neurologic causes occurring in 1 patient (1%) in the embolization group and in 3 patients (2%) in the control group. CONCLUSIONS: Among patients with symptomatic chronic subdural hematoma, adjunctive middle meningeal artery embolization resulted in a lower risk of treatment failure than standard treatment alone, without resulting in an increased incidence of disabling stroke or death in the short term. Further study of longer-term safety outcomes is warranted. (Funded by Balt USA; STEM ClinicalTrials.gov number, NCT04410146.).

Many experiments in the past have demonstrated the requirement of de novo gene expression during the long-term retention of learning and memory. Although previous studies implicated individual genes or genetic pathways in learning and memory, they did not uncover the collective behaviors or patterns of the genes. We have used genome-scale screening to analyze gene expression during spatial learning of rats in the Morris water maze. Our results show distinct temporal gene expression profiles associated with learning and memory. Exogenous administration of one peptide whose sustained increase during memory retention was implicated by microarray analysis, fibroblast growth factor (FGF)-18, improved spatial learning behavior, suggesting that pharmacological modulation of pathways and targets identified may allow new therapeutic approaches for improving learning and memory. Results of this study also suggest that while learning and physical activity involve common groups of genes, the behavior of learning and memory emerges from unique patterns of gene expression across time.

Availability of artificial light and light-emitting devices have altered human temporal life, allowing 24-hour healthcare, commerce and production, and expanding social life around the clock. However, physiology and behavior that evolved in the context of 24 h solar days are frequently perturbed by exposure to artificial light at night. This is particularly salient in the context of circadian rhythms, the result of endogenous biological clocks with a rhythm of ~24 h. Circadian rhythms govern the temporal features of physiology and behavior, and are set to precisely 24 h primarily by exposure to light during the solar day, though other factors, such as the timing of meals, can also affect circadian rhythms. Circadian rhythms are significantly affected by night shift work because of exposure to nocturnal light, electronic devices, and shifts in the timing of meals. Night shift workers are at increased risk for metabolic disorder, as well as several types of cancer. Others who are exposed to artificial light at night or late mealtimes also show disrupted circadian rhythms and increased metabolic and cardiac disorders. It is imperative to understand how disrupted circadian rhythms alter metabolic function to develop strategies to mitigate their negative effects. In this review, we provide an introduction to circadian rhythms, physiological regulation of homeostasis by the suprachiasmatic nucleus (SCN), and SCN-mediated hormones that display circadian rhythms, including melatonin and glucocorticoids. Next, we discuss circadian-gated physiological processes including sleep and food intake, followed by types of disrupted circadian rhythms and how modern lighting disrupts molecular clock rhythms. Lastly, we identify how disruptions to hormones and metabolism can increase susceptibility to metabolic syndrome and risk for cardiovascular diseases, and discuss various strategies to mitigate the harmful consequences associated with disrupted circadian rhythms on human health.

Importance: Understanding geographic and community-level factors associated with suicide can inform targeted suicide prevention efforts. Objectives: To estimate suicide rates and trajectories, assess associated county-level contextual factors, and explore variation across the rural-urban continuum. Design, Setting, and Participants: This cross-sectional study included all individuals aged 25 to 64 years who died by suicide from January 1, 1999, to December 31, 2016, in the United States. Spatial analysis was used to map excess risk of suicide, and longitudinal random-effects models using negative binomial regression tested associations of contextual variables with suicide rates as well as interactions among county-level contextual variables. Data analyses were conducted between January 2019 and July 2019. Exposure: County of residence. Main Outcomes and Measures: Three-year county suicide rates during an 18-year period stratified by rural-urban location. Results: Between 1999 and 2016, 453 577 individuals aged 25 to 64 years died by suicide in the United States. Decedents were primarily male (349 082 [77.0%]) with 101 312 (22.3%) aged 25 to 34 years, 120 157 (26.5%) aged 35 to 44 years, 136 377 (30.1%) aged 45 to 54 years, and 95 771 (21.1%) aged 55 to 64 years. Suicide rates were higher and increased more rapidly in rural than in large metropolitan counties. The highest deprivation quartile was associated with higher suicide rates compared with the lowest deprivation quartile, especially in rural areas, although this association declined during the period studied (rural, 1999-2001: incidence rate ratio [IRR], 1.438; 95% CI, 1.319-1.568; P < .001; large metropolitan, 1999-2001: 1.208; 95% CI, 1.149-1.270; P < .001; rural, 2014-2016: IRR, 1.121; 95% CI, 1.032-1.219; P = .01; large metropolitan, 2014-2016: IRR, 0.942; 95% CI, 0.887-1.001; P = .06). The presence of more gun shops was associated with an increase in county-level suicide rates in all county types except the most rural (rural: IRR, 1.001; 95% CI, 0.999-1.004; P = .40; micropolitan: IRR, 1.005; 95% CI, 1.002-1.007; P < .001; small metropolitan: IRR, 1.010; 95% CI, 1.006-1.014; P < .001; large metropolitan: IRR, 1.012; 95% CI, 1.006-1.018; P < .001). High social capital was associated with lower suicide rates than low social capital (IRR, 0.917; 95% CI, 0.891-0.943; P < .001). High social fragmentation, an increasing percentage of the population without health insurance, and an increasing percentage of veterans in a county were associated with higher suicide rates (high social fragmentation: IRR, 1.077; 95% CI, 1.050-1.103; P < .001; percentage of population without health insurance: IRR, 1.005; 95% CI, 1.004-1.006; P < .001; percentage of veterans: IRR, 1.025; 95% CI, 1.021-1.028; P < .001). Conclusions and Relevance: This study found that suicide rates have increased across the nation and most rapidly in rural counties, which may be more sensitive to the impact of social deprivation than more metropolitan counties. Improving social connectedness, civic opportunities, and health insurance coverage as well as limiting access to lethal means have the potential to reduce suicide rates across the rural-urban continuum.

Spices and herbs often contain active phenolic substances endowed with potent antioxidative properties. We had previously shown that curcumin, the yellow pigment in curry, strongly induced HO-1 expression and activity in rat astrocytes. In the CNS, HO-1 has been reported to operate as a fundamental defensive mechanism for neurons exposed to an oxidant challenge. Treatment of astrocytes with curcumin upregulated expression of HO-1 protein at both cytoplasmic and nuclear levels, as shown by immunofluorescence analysis under laser-scanning confocal microscopy. A significant expression of quinone reductase and glutathione Stransferase, two members of phase II detoxification enzymes, was found in astrocytes exposed to 5–15 µM curcumin. Moreover, the effects of curcumin on HO-1 activity were explored in cultured hippocampal neurons. Elevated expression of HO-1 mRNA and protein were detected after 6 h incubation with 5–25 µM curcumin. Higher concentrations of curcumin (50–100 µM) caused a substantial cytotoxic effect with no change in HO-1 protein expression. Interestingly, pre-incubation (18 h) with curcumin resulted in an enhanced cellular resistance to glucose oxidase-mediated oxidative damage; this cytoprotective effect was considerably attenuated by zinc protoporphyrin IX, an inhibitor of heme oxygenase activity. This study gives additional support to the possible use of curcumin as a dietary preventive agent against oxidative stress-related diseases.

Alzheimer's disease (AD) is characterized by accumulation of the neurotoxic peptide β-amyloid, which is produced by proteolysis of amyloid precursor protein (APP). APP is a large membrane-bound copper-binding protein that is essential in maintaining synaptic function and may play a role in synaptogenesis. β-Amyloid has been shown to contribute to the oxidative stress that accompanies AD. Later stages of AD are characterized by neuronal apoptosis. However, the biochemical function of APP and the mechanism of the toxicity of β-amyloid are still unclear. In this study, we show that both β-amyloid and APP can oxidize cholesterol to form 7β-hydroxycholesterol, a proapoptotic oxysterol that was neurotoxic at nanomolar concentrations. 7β-Hydroxycholesterol inhibited secretion of soluble APP from cultured rat hippocampal H19–7/IGF-IR neuronal cells and inhibited tumor necrosis factor-α-converting enzyme α-secretase activity but had no effect on β-site APP-cleaving enzyme 1 activity. 7β-Hydroxycholesterol was also a potent inhibitor of α-protein kinase C, with a Ki of ∼0.2 nm. The rate of reaction between cholesterol and β-amyloid was comparable to the rates of cholesterol-metabolizing enzymes (kcat = 0.211 min- 1The abbreviations used are: AD, Alzheimer's disease; APP, amyloid precursor protein; apoE, apolipoprotein E; PKC, protein kinase C; LDL, low density lipoprotein; HPLC, high-performance liquid chromatography; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; Bis-Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)-propane-1,3-diol; TACE, tumor necrosis factor-α-converting enzyme; sAPP, soluble amylold precursor protein; BACE1, β-site APP-cleaving enzyme. 1The abbreviations used are: AD, Alzheimer's disease; APP, amyloid precursor protein; apoE, apolipoprotein E; PKC, protein kinase C; LDL, low density lipoprotein; HPLC, high-performance liquid chromatography; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; Bis-Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)-propane-1,3-diol; TACE, tumor necrosis factor-α-converting enzyme; sAPP, soluble amylold precursor protein; BACE1, β-site APP-cleaving enzyme.). The rate of production of 7β-hydroxycholesterol by APP was ∼200 times lower than by β-amyloid. Oxidation of cholesterol was accompanied by stoichiometric production of hydrogen peroxide and required divalent copper. The results suggest that a function of APP may be to produce low levels of 7-hydroxycholesterol. Higher levels produced by β-amyloid could contribute to the oxidative stress and cell loss observed in Alzheimer's disease. Alzheimer's disease (AD) is characterized by accumulation of the neurotoxic peptide β-amyloid, which is produced by proteolysis of amyloid precursor protein (APP). APP is a large membrane-bound copper-binding protein that is essential in maintaining synaptic function and may play a role in synaptogenesis. β-Amyloid has been shown to contribute to the oxidative stress that accompanies AD. Later stages of AD are characterized by neuronal apoptosis. However, the biochemical function of APP and the mechanism of the toxicity of β-amyloid are still unclear. In this study, we show that both β-amyloid and APP can oxidize cholesterol to form 7β-hydroxycholesterol, a proapoptotic oxysterol that was neurotoxic at nanomolar concentrations. 7β-Hydroxycholesterol inhibited secretion of soluble APP from cultured rat hippocampal H19–7/IGF-IR neuronal cells and inhibited tumor necrosis factor-α-converting enzyme α-secretase activity but had no effect on β-site APP-cleaving enzyme 1 activity. 7β-Hydroxycholesterol was also a potent inhibitor of α-protein kinase C, with a Ki of ∼0.2 nm. The rate of reaction between cholesterol and β-amyloid was comparable to the rates of cholesterol-metabolizing enzymes (kcat = 0.211 min- 1The abbreviations used are: AD, Alzheimer's disease; APP, amyloid precursor protein; apoE, apolipoprotein E; PKC, protein kinase C; LDL, low density lipoprotein; HPLC, high-performance liquid chromatography; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; Bis-Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)-propane-1,3-diol; TACE, tumor necrosis factor-α-converting enzyme; sAPP, soluble amylold precursor protein; BACE1, β-site APP-cleaving enzyme. 1The abbreviations used are: AD, Alzheimer's disease; APP, amyloid precursor protein; apoE, apolipoprotein E; PKC, protein kinase C; LDL, low density lipoprotein; HPLC, high-performance liquid chromatography; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; Bis-Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)-propane-1,3-diol; TACE, tumor necrosis factor-α-converting enzyme; sAPP, soluble amylold precursor protein; BACE1, β-site APP-cleaving enzyme.). The rate of production of 7β-hydroxycholesterol by APP was ∼200 times lower than by β-amyloid. Oxidation of cholesterol was accompanied by stoichiometric production of hydrogen peroxide and required divalent copper. The results suggest that a function of APP may be to produce low levels of 7-hydroxycholesterol. Higher levels produced by β-amyloid could contribute to the oxidative stress and cell loss observed in Alzheimer's disease. Several lines of evidence have implicated a role for cholesterol in Alzheimer's disease (AD). 1The abbreviations used are: AD, Alzheimer's disease; APP, amyloid precursor protein; apoE, apolipoprotein E; PKC, protein kinase C; LDL, low density lipoprotein; HPLC, high-performance liquid chromatography; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid; Bis-Tris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)-propane-1,3-diol; TACE, tumor necrosis factor-α-converting enzyme; sAPP, soluble amylold precursor protein; BACE1, β-site APP-cleaving enzyme. Elevated serum cholesterol is associated with increased risk for AD (1Evans R.M. Hui S. Perkins A. Lahiri D.K. Poirier J. Farlow M.R. Neurology. 2004; 62: 1869-1871Crossref PubMed Scopus (86) Google Scholar, 2Puglielli L. Tanzi R.E. Kovacs D.M. Nat. Neurosci. 2003; 6: 345-351Crossref PubMed Scopus (700) Google Scholar). Feeding cholesterol and copper to rabbits produces some of the pathological signs reminiscent of Alzheimer's disease, including amyloid-like plaques, and interferes with the ability of rabbits to perform difficult memory tasks (3Sparks D.L. Schreurs B.G. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 11065-11069Crossref PubMed Scopus (401) Google Scholar). The ϵ4 mutant in the gene for apolipoprotein E (apoE), an important cholesterol transport protein associated with low density lipoprotein (LDL), has been shown to be a risk factor for Alzheimer's disease, and cholesterol-lowering drugs reduce the prevalence of AD. Cholesterol can also regulate the generation of the toxic β-amyloid peptide in affected brain regions and can inhibit β-amyloid clearance. Aberrations in cholesterol transport produced by redistribution of presenilin have been shown to increase cellular levels of β-amyloid (4Burns M. Gaynor K. Olm V. Mercken M. LaFrancois J. Wang L. Mathews P.M. Noble W. Matsuoka Y. Duff K. J. Neurosci. 2003; 23: 5645-5649Crossref PubMed Google Scholar). Much attention has also focused on β-amyloid, a neurotoxic peptide produced by proteolysis of APP. APP fragments can regulate cell excitability, synaptic transmission, and long term potentiation. Soluble β-amyloid inactivates specific voltage-dependent K+ channels (5Etcheberrigaray R. Ito E. Kim C.S. Alkon D.L. Science. 1994; 264: 276-279Crossref PubMed Scopus (178) Google Scholar) and activates others (6Furukawa K. Barger S.W. Blalock E.M. Mattson M.P. Nature. 1996; 379: 74-78Crossref PubMed Scopus (300) Google Scholar). The parent protein, APP, is an integral membrane copper-binding protein (7White A.R. Multhaup G. Maher F. Bellingham S. Camakaris J. Zheng H. Bush A.I. Beyreuther K. Masters C.L. Cappai R. J. Neurosci. 2002; 19: 9170-9179Crossref Google Scholar) found in the CNS and in a variety of other cells, including epithelial cells. At least eight alternatively spliced forms of APP are known (8Sandbrink R. Masters C.L. Beyreuther K. Annu. N. Y. Acad. Sci. 1996; 777: 281-287Crossref PubMed Scopus (83) Google Scholar, 9Rockenstein E.M. McConlogue L. Tan H. Power M. Masliah E. Mucke L. J. Biol. Chem. 1995; 270: 257-267Abstract Full Text Full Text PDF Scopus (220) Google Scholar). Zou et al. (10Zou K. Gong J.S. Yanagisawa K. Michikawa M. J. Neurosci. 2002; 22: 4833-4841Crossref PubMed Google Scholar) suggested that monomeric β-amyloid behaves as an antioxidant, whereas oligomerized β-amyloid loses its antioxidant activity. It was shown that cholesterol and monomeric β-amyloid protect against apoptosis (11Sponne I. Fifre A. Kriem B. Koziel V. Bihain B. Oster T. Olivier J.L. Pillot T. J. 2004; PubMed Scopus Google Scholar). also may be a factor in AD. levels are increased in of APP A.R. R. Camakaris J. Zheng H. Bush A.I. Multhaup G. Beyreuther K. Masters C.L. Cappai R. PubMed Scopus Google that APP could be a of copper Multhaup G. A.R. Beyreuther K. Masters C.L. Cappai R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). copper β-amyloid production S. A. A. T. R. A. K. M. Multhaup G. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: PubMed Scopus Google Scholar). APP copper with and to Multhaup G. A.R. Beyreuther K. Masters C.L. Cappai R. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, C.S. D.M. Tanzi R.E. Bush A.I. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C.S. Tanzi R.E. Bush A.I. J. PubMed Scopus Google Scholar). It has been suggested that APP may function as a Tanzi R.E. Bush A.I. N. Y. Acad. Sci. 2004; PubMed Scopus Google Scholar) as an antioxidant, of its ability to copper C.S. T. H. G. 2003; PubMed Scopus Google Scholar, A. W. V. S. S. U. Biol. PubMed Scopus Google and was that of β-amyloid to oxidative stress C.S. T. H. G. 2003; PubMed Scopus Google Scholar, A. W. V. S. S. U. Biol. PubMed Scopus Google Scholar). The and in the of G. T. A. L. E. R. Masters C.L. Beyreuther K. PubMed Scopus Google Scholar). of APP copper A.R. Multhaup G. R. Beyreuther K. Masters C.L. Cappai R. J. Neurosci. 22: Google that APP may toxic of It was that this oxidative copper β-amyloid in cells T. J. Cappai R. Masters C.L. Beyreuther K. Multhaup G. Biol. Google Scholar). of Alzheimer's disease is oxidative β-Amyloid produces oxidative stress by by the of β-amyloid at which can with in a K. Mattson M.P. M. M. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google by by with to the and of and the β-Amyloid was also to oxidative stress by from cholesterol A.R. Cappai R. Masters C.L. Tanzi R.E. Bush A.I. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). have been found in of Alzheimer's A. M. M. V. R. Biol. 2002; PubMed Scopus Google Scholar). 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Several neurodegenerative disorders are associated with oxidative stress that is manifested by lipid peroxidation, protein oxidation and other markers. Included in these disorders in which oxidative stress is thought to play an important role in their pathogenesis are Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), tardive dyskinesia, Huntington's disease (HD), and multiple sclerosis. This review presents some of the chemistry of vitamin E as an antioxidant and summarizes studies in which vitamin E has been employed in these disorders and models thereof.

Quantum confined materials have been extensively studied for photoluminescent applications. Due to intrinsic limitations of low biocompatibility and challenging modulation, the utilization of conventional inorganic quantum confined photoluminescent materials in bio-imaging and bio-machine interface faces critical restrictions. Here, we present aromatic cyclo-dipeptides that dimerize into quantum dots, which serve as building blocks to further self-assemble into quantum confined supramolecular structures with diverse morphologies and photoluminescence properties. Especially, the emission can be tuned from the visible region to the near-infrared region (420 nm to 820 nm) by modulating the self-assembly process. Moreover, no obvious cytotoxic effect is observed for these nanostructures, and their utilization for in vivo imaging and as phosphors for light-emitting diodes is demonstrated. The data reveal that the morphologies and optical properties of the aromatic cyclo-dipeptide self-assemblies can be tuned, making them potential candidates for supramolecular quantum confined materials providing biocompatible alternatives for broad biomedical and opto-electric applications.

Loss of synapses has been correlated with dementia in Alzheimer's disease (AD) as an early event during the disease progression. Hence, synaptogenesis and neurogenesis in adulthood could serve as a therapeutic target for the prevention and treatment of AD. Recently, we have demonstrated enhanced hippocampal neurogenesis by oral administration of Ginkgo biloba extract (EGb 761) to a mouse model of AD. This study aims to identify the constituents that contribute to EGb 761-induced neurogenesis. Among the constituents tested, bilobalide and quercetin significantly increased cell proliferation in the hippocampal neurons in a dose-dependent manner. Bilobalide and quercetin also enhanced phosphorylation of cyclic-AMP Response Element Binding Protein (CREB) in these cells, and elevated the levels of pCREB and, brain-derived neurotrophic factor in mice brain. Immunofluorescence staining of synaptic markers shows remarkable dendritic processes in hippocampal neurons treated with either quercetin or bilobalide. Furthermore, both constituents restored amyloid-beta oligomers (also known as ADDL)-induced synaptic loss and phosphorylation of CREB. The present findings suggest that enhanced neurogenesis and synaptogenesis by bilobalide and quercetin may share a common final signaling pathway mediated by phosphorylation of CREB. Despite a recent report showing that EGb 761 was insufficient in prevent dementia, its constituents still warrant future investigation.

Accumulation of amyloid beta (Abeta) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of Abeta. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied Abeta oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to Abeta aggregation and subsequent synaptic loss.

Understanding how people rate their confidence is critical for the characterization of a wide range of perceptual, memory, motor and cognitive processes. To enable the continued exploration of these processes, we created a large database of confidence studies spanning a broad set of paradigms, participant populations and fields of study. The data from each study are structured in a common, easy-to-use format that can be easily imported and analysed using multiple software packages. Each dataset is accompanied by an explanation regarding the nature of the collected data. At the time of publication, the Confidence Database (which is available at https://osf.io/s46pr/) contained 145 datasets with data from more than 8,700 participants and almost 4 million trials. The database will remain open for new submissions indefinitely and is expected to continue to grow. Here we show the usefulness of this large collection of datasets in four different analyses that provide precise estimations of several foundational confidence-related effects.