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Article: A randomized feasibility trial of the modified Atkins diet in older adults with mild cognitive impairment due to Alzheimer's disease.

Buchholz, Alison / Deme, Pragney / Betz, Joshua F / Brandt, Jason / Haughey, Norman / Cervenka, Mackenzie C

2024 Volume 15, Page(s) 1182519

Abstract: Background: Alzheimer's disease (AD) is increasing in prevalence, but effective treatments for its cognitive impairment remain severely limited. This study investigates the impact of ketone body production through dietary manipulation on memory in ... ...

Abstract	Background: Alzheimer's disease (AD) is increasing in prevalence, but effective treatments for its cognitive impairment remain severely limited. This study investigates the impact of ketone body production through dietary manipulation on memory in persons with mild cognitive impairment due to early AD and explores potential mechanisms of action. Methods: We conducted a 12-week, parallel-group, controlled feasibility trial of a ketogenic diet, the modified Atkins diet (MAD), compared to a control diet in patients with cognitive impairments attributed to AD. We administered neuropsychological assessments, including memory tests, and collected blood samples at baseline and after 12 weeks of intervention. We performed untargeted lipidomic and targeted metabolomic analyses on plasma samples to detect changes over time. Results: A total of 839 individuals were screened to yield 38 randomized participants, with 20 assigned to receive MAD and 18 assigned to receive a control diet. Due to attrition, only 13 in the MAD arm and nine in the control arm were assessed for the primary endpoint, with two participants meeting ketosis levels used to define MAD adherence criteria. The average change from baseline in the Memory Composite Score was 1.37 (95% CI: -0.87, 4.90) points higher in the MAD group compared to the control group. The effect size of the intervention on baseline MAD change was moderate (Cohen's Conclusions: Attrition was greatest between baseline and week 6. All participants retained at week 6 completed the study. Despite low rates of adherence by criteria defined
MeSH term(s)	Humans ; Aged ; Alzheimer Disease/complications ; Diet, High-Protein Low-Carbohydrate ; Feasibility Studies ; Cognitive Dysfunction/etiology ; Fatty Acids
Chemical Substances	Fatty Acids
Language	English
Publishing date	2024-03-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2024.1182519
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Article: Neonate personality affects early-life resource acquisition in a large social mammal.

Amin, Bawan / Jennings, Dómhnall J / Norman, Alison / Ryan, Andrew / Ioannidis, Vasiliki / Magee, Alice / Haughey, Hayley-Anne / Haigh, Amy / Ciuti, Simone

Behavioral ecology : official journal of the International Society for Behavioral Ecology

2022 Volume 33, Issue 5, Page(s) 1025–1035

Abstract: Although it is widely acknowledged that animal personality plays a key role in ecology, current debate focuses on the exact role of personality in mediating life-history trade-offs. Crucial for our understanding is the relationship between personality ... ...

Abstract	Although it is widely acknowledged that animal personality plays a key role in ecology, current debate focuses on the exact role of personality in mediating life-history trade-offs. Crucial for our understanding is the relationship between personality and resource acquisition, which is poorly understood, especially during early stages of development. Here we studied how among-individual differences in behavior develop over the first 6 months of life, and their potential association with resource acquisition in a free-ranging population of fallow deer (
Language	English
Publishing date	2022-08-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	1496189-1
ISSN	1465-7279 ; 1045-2249
ISSN (online)	1465-7279
ISSN	1045-2249
DOI	10.1093/beheco/arac072
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Article ; Online: Neuronal deletion of nSMase2 reduces the production of Aβ and directly protects neurons.

Tohumeken, Sehmus / Deme, Pragney / Yoo, Seung Wan / Gupta, Sujasha / Rais, Rana / Slusher, Barbara S / Haughey, Norman J

Neurobiology of disease

2023 Volume 177, Page(s) 105987

Abstract: Extracellular vesicles (EVs) have been proposed to regulate the deposition of Aβ. Multiple publications have shown that APP, amyloid processing enzymes and Aβ peptides are associated with EVs. However, very little Aβ is associated with EVs compared with ... ...

Abstract	Extracellular vesicles (EVs) have been proposed to regulate the deposition of Aβ. Multiple publications have shown that APP, amyloid processing enzymes and Aβ peptides are associated with EVs. However, very little Aβ is associated with EVs compared with the total amount Aβ present in human plasma, CSF, or supernatants from cultured neurons. The involvement of EVs has largely been inferred by pharmacological inhibition or whole body deletion of the sphingomyelin hydrolase neutral sphingomyelinase-2 (nSMase2) that is a key regulator for the biogenesis of at-least one population of EVs. Here we used a Cre-Lox system to selectively delete nSMase2 from pyramidal neurons in APP/PS1 mice (APP/PS1-SMPD3-Nex1) and found a ∼ 70% reduction in Aβ deposition at 6 months of age and ∼ 35% reduction at 12 months of age in both cortex and hippocampus. Brain ceramides were increased in APP/PS1 compared with Wt mice, but were similar to Wt in APP/PS1-SMPD3-Nex1 mice suggesting that elevated brain ceramides in this model involves neuronally expressed nSMase2. Reduced levels of PSD95 and deficits of long-term potentiation in APP/PS1 mice were normalized in APP/PS1-SMPD3-Nex1 mice. In contrast, elevated levels of IL-1β, IL-8 and TNFα in APP/PS1 mice were not normalized in APP/PS1-SMPD3-Nex1 mice compared with APP/PS1 mice. Mechanistic studies showed that the size of liquid ordered membrane microdomains was increased in APP/PS1 mice, as were the amounts of APP and BACE1 localized to these microdomains. Pharmacological inhibition of nSMase2 activity with PDDC reduced the size of the liquid ordered membrane microdomains, reduced the localization of APP with BACE1 and reduced the production of Aβ
MeSH term(s)	Mice ; Humans ; Animals ; Alzheimer Disease ; Amyloid Precursor Protein Secretases ; Mice, Transgenic ; Aspartic Acid Endopeptidases ; Amyloid beta-Peptides ; Neurons ; Amyloid beta-Protein Precursor/genetics ; Presenilin-1 ; Disease Models, Animal ; Sphingomyelin Phosphodiesterase/genetics
Chemical Substances	Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Presenilin-1 ; Smpd3 protein, mouse (EC 3.1.4.12) ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12)
Language	English
Publishing date	2023-01-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2023.105987
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Article ; Online: MEAnalyzer - a Spike Train Analysis Tool for Multi Electrode Arrays.

Dastgheyb, Raha M / Yoo, Seung-Wan / Haughey, Norman J

Neuroinformatics

2019 Volume 18, Issue 1, Page(s) 163–179

Abstract: Despite a multitude of commercially available multi-electrode array (MEA) systems that are each capable of rapid data acquisition from cultured neurons or slice cultures, there is a general lack of available analysis tools. These analysis gaps restrict ... ...

Abstract	Despite a multitude of commercially available multi-electrode array (MEA) systems that are each capable of rapid data acquisition from cultured neurons or slice cultures, there is a general lack of available analysis tools. These analysis gaps restrict the efficient extraction of meaningful physiological features from data sets, and limit interpretation of how experimental manipulations modify neural network activity. Here, we present the development of a user-friendly, publicly-available software called MEAnalyzer. This software contains several spike train analysis methods including relevant statistical calculations, periodicity analysis, functional connectivity analysis, and advanced data visualizations in a user-friendly graphical user interface that requires no coding from the user. Widespread availability of this user friendly and mathematically advanced program will stimulate and enhance the use of MEA technologies.
MeSH term(s)	Action Potentials/physiology ; Algorithms ; Animals ; Brain/physiology ; Electrophysiology/methods ; Microelectrodes ; Neurons/physiology ; Software
Language	English
Publishing date	2019-07-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2111941-7
ISSN	1559-0089 ; 1539-2791
ISSN (online)	1559-0089
ISSN	1539-2791
DOI	10.1007/s12021-019-09431-0
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Article ; Online: Author Correction: Palmitate and pyruvate carbon flux in response to choline and methionine in bovine neonatal hepatocytes.

Chandler, T L / Erb, S J / Myers, William A / Deme, Pragney / Haughey, Norman J / McFadden, J W / White, H M

Scientific reports

2021 Volume 11, Issue 1, Page(s) 8014

Language	English
Publishing date	2021-04-07
Publishing country	England
Document type	Published Erratum
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-86713-1
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Article ; Online: Sphingolipids in neurodegeneration.

Haughey, Norman J

Neuromolecular medicine

2010 Volume 12, Issue 4, Page(s) 301–305

Abstract: ... in regulating normal neural activity. Likewise, we are beginning to understand how perturbations in sphingolipid ...

Abstract	Although the brain contains a high content of sphingolipids, we know relatively little about the roles that sphingolipids play in regulating neural functions. Once regarded only for their structural roles in maintaining the integrity of cellular and sub-cellular compartments, it is now apparent that many sphingolipid species are biologically active and play important roles in regulating signaling events. Recent technological and scientific advances are rapidly increasing our knowledge of the roles that sphingolipids play in regulating normal neural activity. Likewise, we are beginning to understand how perturbations in sphingolipid metabolism contribute to the pathogenesis of a variety of neurodegenerative conditions. In this special issue of NeuroMolecular Medicine, we present a series of review articles that summarize new and emerging technologies for the analysis of sphingolipids, sphingolipid metabolic pathways, and how dysfunctions in sphingolipid metabolism contribute to neurodegeneration in lysosomal storage disorders, Alzheimer's disease and Multiple Sclerosis.
MeSH term(s)	Alzheimer Disease/metabolism ; Brain/metabolism ; Glycosphingolipids/metabolism ; Humans ; Lysosomal Storage Diseases/metabolism ; Membrane Microdomains/metabolism ; Multiple Sclerosis/metabolism ; Neurodegenerative Diseases/metabolism ; Synaptic Transmission
Chemical Substances	Glycosphingolipids
Language	English
Publishing date	2010-08-25
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2077809-0
ISSN	1559-1174 ; 1535-1084
ISSN (online)	1559-1174
ISSN	1535-1084
DOI	10.1007/s12017-010-8135-5
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Article ; Online: Inhibition of neutral sphingomyelinase 2 impairs HIV-1 envelope formation and substantially delays or eliminates viral rebound.

Yoo, Seung-Wan / Waheed, Abdul A / Deme, Pragney / Tohumeken, Sehmus / Rais, Rana / Smith, Matthew D / DeMarino, Catherine / Calabresi, Peter A / Kashanchi, Fatah / Freed, Eric O / Slusher, Barbara S / Haughey, Norman J

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 28, Page(s) e2219543120

Abstract: Although HIV-1 Gag is known to drive viral assembly and budding, the precise mechanisms by which the lipid composition of the plasma membrane is remodeled during assembly are incompletely understood. Here, we provide evidence that the sphingomyelin ... ...

Abstract	Although HIV-1 Gag is known to drive viral assembly and budding, the precise mechanisms by which the lipid composition of the plasma membrane is remodeled during assembly are incompletely understood. Here, we provide evidence that the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) interacts with HIV-1 Gag and through the hydrolysis of sphingomyelin creates ceramide that is necessary for proper formation of the viral envelope and viral maturation. Inhibition or depletion of nSMase2 resulted in the production of noninfectious HIV-1 virions with incomplete Gag lattices lacking condensed conical cores. Inhibition of nSMase2 in HIV-1-infected humanized mouse models with a potent and selective inhibitor of nSMase2 termed PDDC [phenyl(R)-(1-(3-(3,4-dimethoxyphenyl)-2, 6-dimethylimidazo[1,2-b]pyridazin-8-yl) pyrrolidin-3-yl)-carbamate] produced a linear reduction in levels of HIV-1 in plasma. If undetectable plasma levels of HIV-1 were achieved with PDDC treatment, viral rebound did not occur for up to 4 wk when PDDC was discontinued. In vivo and tissue culture results suggest that PDDC selectively kills cells with actively replicating HIV-1. Collectively, this work demonstrates that nSMase2 is a critical regulator of HIV-1 replication and suggests that nSMase2 could be an important therapeutic target with the potential to kill HIV-1-infected cells.
MeSH term(s)	Mice ; Animals ; Sphingomyelin Phosphodiesterase/metabolism ; HIV-1/metabolism ; Sphingomyelins/metabolism ; Cell Membrane/metabolism
Chemical Substances	Sphingomyelin Phosphodiesterase (EC 3.1.4.12) ; Sphingomyelins ; pyrenedodecanoylcarnitine (93255-34-6)
Language	English
Publishing date	2023-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2219543120
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Article ; Online: Neutral sphingomyelinase 2 is required for HIV-1 maturation.

Waheed, Abdul A / Zhu, Yanan / Agostino, Eva / Naing, Lwar / Hikichi, Yuta / Soheilian, Ferri / Yoo, Seung-Wan / Song, Yun / Zhang, Peijun / Slusher, Barbara S / Haughey, Norman J / Freed, Eric O

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 28, Page(s) e2219475120

Abstract: HIV-1 assembly occurs at the inner leaflet of the plasma membrane (PM) in highly ordered membrane microdomains. The size and stability of membrane microdomains is regulated by activity of the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) ... ...

Abstract	HIV-1 assembly occurs at the inner leaflet of the plasma membrane (PM) in highly ordered membrane microdomains. The size and stability of membrane microdomains is regulated by activity of the sphingomyelin hydrolase neutral sphingomyelinase 2 (nSMase2) that is localized primarily to the inner leaflet of the PM. In this study, we demonstrate that pharmacological inhibition or depletion of nSMase2 in HIV-1-producer cells results in a block in the processing of the major viral structural polyprotein Gag and the production of morphologically aberrant, immature HIV-1 particles with severely impaired infectivity. We find that disruption of nSMase2 also severely inhibits the maturation and infectivity of other primate lentiviruses HIV-2 and simian immunodeficiency virus, has a modest or no effect on nonprimate lentiviruses equine infectious anemia virus and feline immunodeficiency virus, and has no effect on the gammaretrovirus murine leukemia virus. These studies demonstrate a key role for nSMase2 in HIV-1 particle morphogenesis and maturation.
MeSH term(s)	Animals ; Cats ; Horses ; Mice ; HIV-1/physiology ; Sphingomyelin Phosphodiesterase/metabolism ; Virus Assembly ; Lentivirus ; Infectious Anemia Virus, Equine
Chemical Substances	Sphingomyelin Phosphodiesterase (EC 3.1.4.12)
Language	English
Publishing date	2023-07-05
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2219475120
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Article ; Online: Involvement of organelles and inter-organellar signaling in the pathogenesis of HIV-1 associated neurocognitive disorder and Alzheimer's disease.

Khan, Nabab / Haughey, Norman J / Nath, Avindra / Geiger, Jonathan D

Brain research

2019 Volume 1722, Page(s) 146389

Abstract: Endolysosomes, mitochondria, peroxisomes, endoplasmic reticulum, and plasma membranes are now known to physically and functionally interact with each other. Such findings of inter-organellar signaling and communication has led to a resurgent interest in ... ...

Abstract	Endolysosomes, mitochondria, peroxisomes, endoplasmic reticulum, and plasma membranes are now known to physically and functionally interact with each other. Such findings of inter-organellar signaling and communication has led to a resurgent interest in cell biology and an increased appreciation for the physiological actions and pathological consequences of the dynamic physical and chemical communications occurring between intracellular organelles. Others and we have shown that HIV-1 proteins implicated in the pathogenesis of neuroHIV and that Alzheimer's disease both affects the structure and function of intracellular organelles. Intracellular organelles are highly mobile, and their intracellular distribution almost certainly affects their ability to interact with other organelles and to regulate such important physiological functions as endolysosome acidification, cell motility, and nutrient homeostasis. Indeed, compounds that acidify endolysosomes cause endolysosomes to exhibit a mainly perinuclear pattern while compounds that de-acidify endolysosomes cause these organelles to exhibit a larger profile as well as movement towards plasma membranes. Endolysosome pH might be an early event in the pathogenesis of neuroHIV and Alzheimer's disease and in terms of organellar biology endolysosome changes might be upstream of HIV-1 protein-induced changes to other organelles. Thus, inter-organellar signaling mechanisms might be involved in the pathogenesis of neuroHIV and other neurological disorders, and a better understanding of inter-organellar signaling might lead to improved therapeutic strategies.
MeSH term(s)	Alzheimer Disease/metabolism ; Animals ; Brain/metabolism ; Endoplasmic Reticulum/metabolism ; HIV Infections/metabolism ; HIV-1/metabolism ; Humans ; Mitochondria/metabolism ; Neurocognitive Disorders/metabolism ; Neurocognitive Disorders/virology ; Neurons/metabolism ; Organelles/metabolism ; Signal Transduction
Language	English
Publishing date	2019-08-16
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2019.146389
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Article: Characterization of the Plasma Lipidome in Dairy Cattle Transitioning from Gestation to Lactation: Identifying Novel Biomarkers of Metabolic Impairment.

Rico, Jorge Eduardo / Saed Samii, Sina / Zang, Yu / Deme, Pragney / Haughey, Norman J / Grilli, Ester / McFadden, Joseph W

Metabolites

2021 Volume 11, Issue 5

Abstract: ... our understanding of normal and dysfunctional metabolism, and lead to nutritional interventions that improve health ...

Abstract	The discovery of novel biomarkers for peripartal diseases in dairy cows can improve our understanding of normal and dysfunctional metabolism, and lead to nutritional interventions that improve health and milk production. Our objectives were to characterize the plasma lipidome and identify metabolites associated with common markers of metabolic disease in peripartal dairy cattle. Multiparous Holstein cows (
Language	English
Publishing date	2021-04-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662251-8
ISSN	2218-1989
ISSN	2218-1989
DOI	10.3390/metabo11050290
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