Alzheimer's disease (AD) is an age-related disorder characterized by deposition of amyloid ␤-peptide (A␤) and degeneration of neurons in brain regions such as the hippocampus, resulting in progressive cognitive dysfunction. The pathogenesis of AD is tightly linked to A␤ deposition and oxidative stress, but it remains unclear as to how these factors result in neuronal dysfunction and death. We report alterations in sphingolipid and cholesterol metabolism during normal brain aging and in the brains of AD patients that result in accumulation of long-chain ceramides and cholesterol. Membrane-associated oxidative stress occurs in association with the lipid alterations, and exposure of hippocampal neurons to A␤ induces membrane oxidative stress and the accumulation of ceramide species and cholesterol. Treatment of neurons with ␣-tocopherol or an inhibitor of sphingomyelin synthesis prevents accumulation of ceramides and cholesterol and protects them against death induced by A␤. Our findings suggest a sequence of events in the pathogenesis of AD in which A␤ induces membrane-associated oxidative stress, resulting in perturbed ceramide and cholesterol metabolism which, in turn, triggers a neurodegenerative cascade that leads to clinical disease.amyloid ͉ apoptosis ͉ hippocampus ͉ lipid peroxidation ͉ sphingomyelin C hanges that occur in the brain during aging increase the risk of Alzheimer's disease (AD), a disorder involving the progressive deposition of amyloid ␤-peptide (A␤) and associated degeneration of neurons in brain regions involved in learning and memory (1). Two factors that are believed to contribute to neuronal dysfunction and degeneration in AD are increased oxidative stress and increased production of neurotoxic forms of A␤ (2). Alterations in lipid metabolism may also play roles in AD because the risk of AD is affected by inheritance of different isoforms of apolipoprotein E (3), changes in cholesterol metabolism can affect A␤ production in cell culture and in vivo (4-6), and drugs that lower cholesterol levels may reduce the risk of AD (7,8). However, a direct link between alterations in the metabolism of cholesterol and other membrane lipids in AD has not been established, and it is not known whether and how such lipid alterations might lead to neuronal dysfunction and death.Membrane microdomains that are rich in cholesterol and sphingolipids play important roles in various cellular signaling pathways (9, 10). Sphingomyelin is a major source of ceramides, lipid mediators that are generated when sphingomyelin is cleaved by sphingomyelinases, enzymes activated by inflammatory cytokines (11) and oxidative stress (12). Ceramides play important roles in regulating an array of physiological processes, including cell proliferation and differentiation, and a form of programmed cell death called apoptosis (13). Ceramides have been implicated in the pathological death of neurons that occurs in ischemic stroke (14) and Parkinson's disease (15). In the present study, we document significant increases in levels of m...

Background: The problems of adherence to energy restriction in humans are well known. Objective: To compare the feasibility and effectiveness of intermittent continuous energy (IER) with continuous energy restriction (CER) for weight loss, insulin sensitivity and other metabolic disease risk markers. Design: Randomized comparison of a 25% energy restriction as IER (B2710 kJ/day for 2 days/week) or CER (B6276 kJ/day for 7 days/week) in 107 overweight or obese (mean ( ± s.d.) body mass index 30.6 ( ± 5.1) kg m À2 ) premenopausal women observed over a period of 6 months. Weight, anthropometry, biomarkers for breast cancer, diabetes, cardiovascular disease and dementia risk; insulin resistance (HOMA), oxidative stress markers, leptin, adiponectin, insulin-like growth factor (IGF)-1 and IGF binding proteins 1 and 2, androgens, prolactin, inflammatory markers (high sensitivity C-reactive protein and sialic acid), lipids, blood pressure and brain-derived neurotrophic factor were assessed at baseline and after 1, 3 and 6 months. Results: Last observation carried forward analysis showed that IER and CER are equally effective for weight loss: mean (95% confidence interval ) weight change for IER was À6.4 (À7.9 to À4.8) kg vs À5.6 (À6.9 to À4.4) kg for CER (P-value for difference between groups ¼ 0.4). Both groups experienced comparable reductions in leptin, free androgen index, high-sensitivity C-reactive protein, total and LDL cholesterol, triglycerides, blood pressure and increases in sex hormone binding globulin, IGF binding proteins 1 and 2. Reductions in fasting insulin and insulin resistance were modest in both groups, but greater with IER than with CER; difference between groups for fasting insulin was À1.2 (À1.4 to À1.0) mU ml À1 and for insulin resistance was À1.2 (À1.5 to À1.0) mU mmol À1 l À1 (both P ¼ 0.04). Conclusion: IER is as effective as CER with regard to weight loss, insulin sensitivity and other health biomarkers, and may be offered as an alternative equivalent to CER for weight loss and reducing disease risk.

Neuritic plaques, a pathological hallmark in Alzheimer’s disease (AD) brains, comprise extracellular aggregates of amyloid-beta (Aβ) peptide and degenerating neurites that accumulate autolysosomes. We found that, in the brains of patients with AD and in AD mouse models, Aβ plaque-associated Olig2- and NG2-expressing oligodendrocyte progenitor cells (OPCs), but not astrocytes, microglia, or oligodendrocytes, exhibit a senescence-like phenotype characterized by the upregulation of p21/CDKN1A, p16/INK4/CDKN2A proteins, and senescence-associated β-galactosidase activity. Molecular interrogation of the Aβ plaque environment revealed elevated levels of transcripts encoding proteins involved in OPC function, replicative senescence, and inflammation. Direct exposure of cultured OPCs to aggregating Aβ triggered cell senescence. Senolytic treatment of AD mice selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lessened Aβ load, and ameliorated cognitive deficits. Our findings suggest a role for Aβ-induced OPC cell senescence in neuroinflammation and cognitive deficits in AD, and a potential therapeutic benefit of senolytic treatments.

Multiple organ systems are adversely affected by diabetes, including the brain, which undergoes changes that may increase the risk of cognitive decline. Although diabetes influences the hypothalamic-pituitary-adrenal axis, the role of this neuroendocrine system in diabetes-induced cognitive dysfunction remains unexplored. Here we demonstrate that, in both insulin-deficient rats and insulin-resistant mice, diabetes impairs hippocampus-dependent memory, perforant path synaptic plasticity and adult neurogenesis, and the adrenal steroid corticosterone contributes to these adverse effects. Rats treated with streptozocin have reduced levels of insulin, and exhibit hyperglycemia, increased levels of corticosterone, and impairments in hippocampal neurogenesis, synaptic plasticity and learning. Similar deficits are observed in db/db mice, which are characterized by insulin resistance, elevated corticosterone levels and obesity. Changes in hippocampal plasticity and function in both models are reversed when normal physiological levels of corticosterone are maintained, suggesting that cognitive impairment in diabetes may result from glucocorticoidmediated deficits in neurogenesis and synaptic plasticity. Keywords glucocorticoid; dentate gyrus; streptozotocin; water maze; object recognition As a result of high calorie diets and sedentary lifestyles, diabetes is rapidly becoming more prevalent in Western societies 1 . In addition to its well-known adverse effects on the cardiovascular and peripheral nervous systems, diabetes also appears to negatively impact the brain, increasing the risk of depression and dementia2 , 3 . Human subjects with either type 1 (caused by insulin deficiency) or type 2 (mediated by insulin resistance) diabetes typically exhibit impaired cognitive function compared to age-matched non-diabetic subjects 3,4 . Cognitive deficits have also been documented in studies of rodent models of diabetes. For Supplementary Information accompanies this paper.Competing interests statement. The authors declare that they have no competing financial interests. Conflict of Interest:The authors declare no conflict of interest. NIH Public Access Author ManuscriptNat Neurosci. Author manuscript; available in PMC 2010 August 25. Published in final edited form as:Nat Neurosci. 2008 March ; 11(3): 309-317. doi:10.1038/nn2055. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript example, rats rendered diabetic by treatment with the pancreatic β-cell toxin streptozocin (STZ; a model of type 1 diabetes) exhibit impaired performance in tests of spatial learning ability 5, 6. Similar deficits have been reported in the db/db mouse7, a model of Type 2 diabetes in which obesity, hyperglycemia, and elevations in circulating corticosterone levels arise from a mutation that inactivates the leptin receptor 8 . However, the mechanism(s) responsible for cognitive dysfunction in diabetes has not been established.Within the hippocampus, changes in the strength of synapses between groups of neurons play a critic...

Intermittent energy restriction may result in greater improvements in insulin sensitivity and weight control than daily energy restriction (DER). We tested two intermittent energy and carbohydrate restriction (IECR) regimens, including one which allowed ad libitum protein and fat (IECR þ PF). Overweight women (n 115) aged 20 and 69 years with a family history of breast cancer were randomised to an overall 25 % energy restriction, either as an IECR (2500 -2717 kJ/d, , 40 g carbohydrate/d for 2 d/week) or a 25 % DER (approximately 6000 kJ/d for 7 d/week) or an IECR þ PF for a 3-month weight-loss period and 1 month of weight maintenance (IECR or IECR þ PF for 1 d/week). Insulin resistance reduced with the IECR diets (mean 20·34 (95 % CI 2 0·66, 2 0·02) units) and the IECR þ PF diet (mean 2 0·38 (95 % CI 20·75, 2 0·01) units). Reductions with the IECR diets were significantly greater compared with the DER diet (mean 0·2 (95 % CI 2 0·19, 0·66) mU/unit, P¼0·02). Both IECR groups had greater reductions in body fat compared with the DER group (IECR: mean 2 3·7 (95 % CI 22·5, 24·9) kg, P¼0·007; IECR þ PF: mean 23·7 (95 % CI 2 2·8, 24·7) kg, P¼0·019; DER: mean 22·0 (95 % CI 21·0, 3·0) kg). During the weight maintenance phase, 1 d of IECR or IECR þ PF per week maintained the reductions in insulin resistance and weight. In the short term, IECR is superior to DER with respect to improved insulin sensitivity and body fat reduction. Longer-term studies into the safety and effectiveness of IECR diets are warranted.Key words: Intermittent energy restriction: Low-carbohydrate diets: Weight loss: Daily energy restriction: Insulin resistanceThe global health burden of obesity-related conditions such as diabetes, CVD, dementia and certain cancers, including breast cancer, may be reduced by weight loss and the associated improvements in insulin sensitivity. The difficulties of achieving and sustaining weight loss by energy restriction are well known (1) . Even when reduced weights are maintained, metabolic benefits achieved with weight loss are often attenuated because of non-compliance or adaptation (2 -4) . Effective dietary interventions are needed that promote long-term adherence and sustained beneficial effects on metabolic and disease markers. Such interventions need to be palatable and satiating, meet minimal nutritional requirements, promote loss of fat and preserve lean body mass, ensure long-term safety, be simple to administer and monitor and have widespread public health utility. Multiple dietary approaches have been studied that vary in macronutrient composition (5) and the degree of energy restriction (6) . These typically achieve long-term 5 % weight loss in

Overall dietary energy intake, particularly the consumption of simple sugars such as fructose, has been increasing steadily in Western societies, but the effects of such diets on the brain are poorly understood. Here we used functional and structural assays to characterize the effects of excessive caloric intake on the hippocampus, a brain region important for learning and memory. Rats fed a high-fat, high-glucose diet supplemented with high-fructose corn syrup showed alterations in energy and lipid metabolism similar to clinical diabetes, with elevated fasting glucose and increased cholesterol and triglycerides. Rats maintained on this diet for eight months exhibited impaired spatial learning ability, reduced hippocampal dendritic spine density, and reduced LTP at Schaffer collateral -CA1 synapses. These changes occurred concurrently with reductions in levels of brain-derived neurotrophic factor in the hippocampus. We conclude that a high energy diet reduces hippocampal synaptic plasticity and impairs cognitive function, possibly through BDNF-mediated effects on dendritic spines. Keywordsfructose; hippocampus; long-term potentiation; obesity; diabetes; BDNF; high-fat diet Dietary energy intake has increased steadily in Western societies during the past 50 years resulting in increased obesity, diabetes and cardiovascular disease (Everitt et al., 2006). Simple sugars and saturated fats are believed to be major components of the Western diet that promote obesity and insulin resistance (Gross et al., 2004). Data from clinical, epidemiological and animal studies have suggested that excessive energy intake adversely affects the brain, particularly during aging. Studies suggest that individuals with a high energy intake are at increased risk of Alzheimer's disease (Luschsinger et al., 2002). Animal studies have shown that high-calorie diets impair the structure and function of the hippocampus, a brain region critical for learning and memory (Farr et al., 2008;Greenwood and Winocur, 1990;Kanoski et al., 2007;Molteni et al., 2002;Winocur and Greenwood, 1999;Wu et al., 2004). The adverse effects of high calorie diets on learning and memory have been associated with impaired hippocampal synaptic plasticity and neurogenesis (Farr et al., 2008;Lindqvist et al., 2006), suggesting that the hippocampus may be particularly sensitive to changes in dietary energy intake. In the present study we fed rats a diet high in saturated fats and simple sugars, and supplemented their water with high-fructose corn syrup. This diet increased fasting blood glucose levels and serum cholesterol and triglycerides. Additionally, we found that the diet impairs hippocampusdependent learning, synaptic plasticity, and dendritic spine density. These adverse effects on brain function were associated with reduced levels of BDNF in the hippocampus and suggest that "Western" diets impair synaptic function and cognition by a mechanism involving reductions in BDNF and atrophy of dendritic spines. Detailed description of the methods and procedures us...

Background-Asthma is an increasingly common disorder responsible for considerable morbidity and mortality. Although obesity is a risk factor for asthma and weight loss can improve symptoms, many patients do not adhere to low calorie diets and the impact of dietary restriction on the disease process is unknown.

Recent epidemiological and clinical data suggest that persons with low folic acid levels and elevated homocysteine levels are at increased risk of Alzheimer's disease (AD), but the underlying mechanism is unknown. We tested the hypothesis that impaired one-carbon metabolism resulting from folic acid deficiency and high homocysteine levels promotes accumulation of DNA damage and sensitizes neurons to amyloid beta-peptide (Abeta) toxicity. Incubation of hippocampal cultures in folic acid-deficient medium or in the presence of methotrexate (an inhibitor of folic acid metabolism) or homocysteine induced cell death and rendered neurons vulnerable to death induced by Abeta. Methyl donor deficiency caused uracil misincorporation and DNA damage and greatly potentiated Abeta toxicity as the result of reduced repair of Abeta-induced oxidative modification of DNA bases. When maintained on a folic acid-deficient diet, amyloid precursor protein (APP) mutant transgenic mice, but not wild-type mice, exhibited increased cellular DNA damage and hippocampal neurodegeneration. Levels of Abeta were unchanged in the brains of folate-deficient APP mutant mice. Our data suggest that folic acid deficiency and homocysteine impair DNA repair in neurons, which sensitizes them to oxidative damage induced by Abeta.