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Article ; Online: Accelerated Breakdown of Phosphatidylcholine and Phosphatidylethanolamine Is a Predominant Brain Metabolic Defect in Alzheimer's Disease.

Blusztajn, Jan Krzysztof / Slack, Barbara E

2023 Volume 93, Issue 4, Page(s) 1285–1289

Abstract: Numerous studies have demonstrated defects in multiple metabolic pathways in Alzheimer's disease (AD), detected in autopsy brains and in the cerebrospinal fluid in vivo. However, until the advent of techniques capable of measuring thousands of ... ...

Abstract	Numerous studies have demonstrated defects in multiple metabolic pathways in Alzheimer's disease (AD), detected in autopsy brains and in the cerebrospinal fluid in vivo. However, until the advent of techniques capable of measuring thousands of metabolites in a single sample, it has not been possible to rank the relative magnitude of these abnormalities. A recent study provides evidence that the abnormal turnover of the brain's most abundant phospholipids: phosphatidylcholine and phosphatidylethanolamine, constitutes a major metabolic pathology in AD. We place this observation in a historical context and discuss the implications of a central role for phospholipid metabolism in AD pathogenesis.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Phosphatidylethanolamines/metabolism ; Phosphatidylcholines/metabolism ; Phospholipids/metabolism ; Brain/pathology
Chemical Substances	Phosphatidylethanolamines ; Phosphatidylcholines ; Phospholipids
Language	English
Publishing date	2023-04-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-230061
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Article ; Online: A Narrative Review on Maternal Choline Intake and Liver Function of the Fetus and the Infant; Implications for Research, Policy, and Practice.

Obeid, Rima / Schön, Christiane / Derbyshire, Emma / Jiang, Xinyin / Mellott, Tiffany J / Blusztajn, Jan Krzysztof / Zeisel, Steven H

Nutrients

2024 Volume 16, Issue 2

Abstract: Dietary choline is needed to maintain normal health, including normal liver function in adults. Fatty liver induced by a choline-deficient diet has been consistently observed in human and animal studies. The effect of insufficient choline intake on ... ...

Abstract	Dietary choline is needed to maintain normal health, including normal liver function in adults. Fatty liver induced by a choline-deficient diet has been consistently observed in human and animal studies. The effect of insufficient choline intake on hepatic fat accumulation is specific and reversible when choline is added to the diet. Choline requirements are higher in women during pregnancy and lactation than in young non-pregnant women. We reviewed the evidence on whether choline derived from the maternal diet is necessary for maintaining normal liver function in the fetus and breastfed infants. Studies have shown that choline from the maternal diet is actively transferred to the placenta, fetal liver, and human milk. This maternal-to-child gradient can cause depletion of maternal choline stores and increase the susceptibility of the mother to fatty liver. Removing choline from the diet of pregnant rats causes fatty liver both in the mother and the fetus. The severity of fatty liver in the offspring was found to correspond to the severity of fatty liver in the respective mothers and to the duration of feeding the choline-deficient diet to the mother. The contribution of maternal choline intake in normal liver function of the offspring can be explained by the role of phosphatidylcholine in lipid transport and as a component of cell membranes and the function of choline as a methyl donor that enables synthesis of phosphatidylcholine in the liver. Additional evidence is needed on the effect of choline intake during pregnancy and lactation on health outcomes in the fetus and infant. Most pregnant and lactating women are currently not achieving the adequate intake level of choline through the diet. Therefore, public health policies are needed to ensure sufficient choline intake through adding choline to maternal multivitamin supplements.
MeSH term(s)	Adult ; Infant ; Pregnancy ; Humans ; Female ; Animals ; Rats ; Choline ; Lactation ; Fetus ; Public Policy ; Fatty Liver ; Mothers ; Phosphatidylcholines
Chemical Substances	Choline (N91BDP6H0X) ; Phosphatidylcholines
Language	English
Publishing date	2024-01-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu16020260
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Article: Intrinsic Cholinergic Neurons in the Hippocampus: Fact or Artifact?

Blusztajn, Jan Krzysztof / Rinnofner, Jasmine

Frontiers in synaptic neuroscience

2016 Volume 8, Page(s) 6

Abstract: It is generally agreed that hippocampal acetylcholine (ACh) is synthesized and released exclusively from the terminals of the long-axon afferents whose cell bodies reside in the medial septum and diagonal band. The search for intrinsic cholinergic ... ...

Abstract	It is generally agreed that hippocampal acetylcholine (ACh) is synthesized and released exclusively from the terminals of the long-axon afferents whose cell bodies reside in the medial septum and diagonal band. The search for intrinsic cholinergic neurons in the hippocampus has a long history; however evidence for the existence of these neurons has been inconsistent, with most investigators failing to detect them using in situ hybridization or immunohistochemical staining of the cholinergic markers, choline acetyltransferase (ChAT) or vesicular acetylcholine transporter (VAChT). Advances in the use of bacterial artificial chromosome (BAC) transgenic mice expressing a reporter protein under the control of the genomic elements of the Chat gene (Chat-BAC mice) have facilitated studies of cholinergic neurons. Such mice show robust and faithful expression of the reporter proteins in all known cholinergic cell populations. The availability of the Chat-BAC mice re-ignited interest in hippocampal cholinergic interneurons, because a small number of such reporter-expressing cells is frequently observed in the hippocampus of these mice. However, to date, attempts to confirm that these neurons co-express the endogenous cholinergic marker ChAT, or release ACh, have been unsuccessful. Without such confirmatory evidence it is best to conclude that there are no cholinergic neurons in the hippocampus. Similar considerations apply to other BAC transgenic lines, whose utility as a discovery tool for cell populations heretofore not known to express the genes of interest encoded by the BACs, must be validated by methods that detect expression of the endogenous genes.
Language	English
Publishing date	2016-03-10
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2592086-8
ISSN	1663-3563
ISSN	1663-3563
DOI	10.3389/fnsyn.2016.00006
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Article ; Online: Neuroprotective Actions of Dietary Choline.

Blusztajn, Jan Krzysztof / Slack, Barbara E / Mellott, Tiffany J

Nutrients

2017 Volume 9, Issue 8

Abstract: Choline is an essential nutrient for humans. It is a precursor of membrane phospholipids (e.g., phosphatidylcholine (PC)), the neurotransmitter acetylcholine, and via betaine, the methyl group ... ...

Abstract	Choline is an essential nutrient for humans. It is a precursor of membrane phospholipids (e.g., phosphatidylcholine (PC)), the neurotransmitter acetylcholine, and via betaine, the methyl group donor
Language	English
Publishing date	2017-07-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu9080815
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Article ; Online: Is dietary choline intake related to dementia and Alzheimer's disease risks? Results from the Framingham Heart Study.

Yuan, Jing / Liu, Xue / Liu, Chunyu / Ang, Alvin Fa / Massaro, Joseph / Devine, Sherral A / Auerbach, Sanford H / Blusztajn, Jan Krzysztof / Au, Rhoda / Jacques, Paul F

The American journal of clinical nutrition

2023 Volume 116, Issue 5, Page(s) 1201–1207

Abstract: Background: The positive association of choline for cognition has been reported in both animal and human studies, yet the associations of choline with the risks of incident dementia or Alzheimer's disease (AD) in humans is unclear.: Objectives: Our ... ...

Abstract	Background: The positive association of choline for cognition has been reported in both animal and human studies, yet the associations of choline with the risks of incident dementia or Alzheimer's disease (AD) in humans is unclear. Objectives: Our objective was to test the hypothesis that lower or higher dietary choline intake is associated with increased or decreased, respectively, risks of incident dementia and AD. Methods: Data from the Framingham Heart Study Offspring Cohort exam 5 to exam 9 were used. Participants were free of dementia and stroke, with a valid self-reported 126-item Harvard FFQ at exam 5. The intakes of total choline, its contributing compounds, and betaine were estimated based on a published nutrient database. The intakes were updated at each exam to represent the cumulative average intake across the 5 exams. The associations between dietary choline intakes and incident dementia and AD were examined in mixed-effect Cox proportional hazard models, adjusting for covariates. Results: A total of 3224 participants (53.8% female; mean ± SD age, 54.5 ± 9.7 y) were followed up for a mean ± SD of 16.1 ± 5.1 y (1991-2011). There were 247 incident dementia cases, of which 177 were AD. Dietary choline intake showed nonlinear relationships with incident dementia and AD. After adjusting for covariates, low choline intake (defined as ≤ 219 and ≤ 215 mg/d for dementia and AD, respectively) was significantly associated with incident dementia and incident AD. Conclusions: Low choline intake was associated with increased risks of incident dementia and AD.
MeSH term(s)	Animals ; Humans ; Female ; Adult ; Middle Aged ; Male ; Choline ; Alzheimer Disease/epidemiology ; Alzheimer Disease/etiology ; Betaine ; Eating ; Longitudinal Studies
Chemical Substances	Choline (N91BDP6H0X) ; Betaine (3SCV180C9W)
Language	English
Publishing date	2023-02-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.1093/ajcn/nqac193
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Article ; Online: Cerebral Gray and White Matter Monogalactosyl Diglyceride Levels Rise with the Progression of Alzheimer's Disease.

Blusztajn, Jan Krzysztof / Aytan, Nurgul / Rajendiran, Thekkelnaycke / Mellott, Tiffany J / Soni, Tanu / Burant, Charles F / Serrano, Geidy E / Beach, Thomas G / Lin, Honghuang / Stein, Thor D

Journal of Alzheimer's disease : JAD

2023 Volume 95, Issue 4, Page(s) 1623–1634

Abstract: Background: Multiple studies have reported brain lipidomic abnormalities in Alzheimer's disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is ... ...

Abstract	Background: Multiple studies have reported brain lipidomic abnormalities in Alzheimer's disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression. Objective: Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits. Methods: We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer's Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total n = 288). Results: We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aβ40. Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes-the principal cell type of white matter. Conclusions: Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; White Matter/pathology ; Diglycerides/metabolism ; Brain/pathology ; Aging/pathology ; Gray Matter/pathology ; Disease Progression
Chemical Substances	Diglycerides
Language	English
Publishing date	2023-09-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-230543
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Article ; Online: The Expression of Activin Receptor-Like Kinase 1 (ACVRL1/ALK1) in Hippocampal Arterioles Declines During Progression of Alzheimer's Disease.

Anderson, Kelley E / Bellio, Thomas A / Aniskovich, Emily / Adams, Stephanie L / Blusztajn, Jan Krzysztof / Delalle, Ivana

Cerebral cortex communications

2020 Volume 1, Issue 1, Page(s) tgaa031

Abstract: Cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD)-deposition of beta amyloid (Aβ) within the walls of cerebral blood vessels-typically accompanies Aβ buildup in brain parenchyma and causes abnormalities in vessel structure and function. We ... ...

Abstract	Cerebral amyloid angiopathy (CAA) in Alzheimer's disease (AD)-deposition of beta amyloid (Aβ) within the walls of cerebral blood vessels-typically accompanies Aβ buildup in brain parenchyma and causes abnormalities in vessel structure and function. We recently demonstrated that the immunoreactivity of activin receptor-like kinase 1 (ALK1), the type I receptor for circulating BMP9/BMP10 (bone morphogenetic protein) signaling proteins, is reduced in advanced, but not early stages of AD in CA3 pyramidal neurons. Here we characterize vascular expression of ALK1 in the context of progressive AD pathology accompanied by amyloid angiopathy in postmortem hippocampi using immunohistochemical methods. Hippocampal arteriolar wall ALK1 signal intensity was 35% lower in AD patients (Braak and Braak Stages IV and V [BBIV-V]; clinical dementia rating [CDR1-2]) as compared with subjects with early AD pathologic changes but either cognitively intact or with minimal cognitive impairment (BBIII; CDR0-0.5). The intensity of Aβ signal in arteriolar walls was similar in all analyzed cases. These data suggest that, as demonstrated previously for specific neuronal populations, ALK1 expression in blood vessels is also vulnerable to the AD pathophysiologic process, perhaps related to CAA. However, cortical arterioles may remain responsive to the ALK1 ligands, such as BMP9 and BMP10 in early and moderate AD.
Language	English
Publishing date	2020-07-28
Publishing country	United States
Document type	Journal Article
ISSN	2632-7376
ISSN (online)	2632-7376
DOI	10.1093/texcom/tgaa031
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Article ; Online: Choline: The Neurocognitive Essential Nutrient of Interest to Obstetricians and Gynecologists.

Wallace, Taylor C / Blusztajn, Jan Krzysztof / Caudill, Marie A / Klatt, Kevin C / Zeisel, Steven H

Journal of dietary supplements

2019 Volume 17, Issue 6, Page(s) 733–752

Abstract: Choline is an essential nutrient for proper liver, muscle, and brain functions as well as for lipid metabolism and cellular membrane composition and repair. Humans can produce small amounts of choline via the hepatic ... ...

Abstract	Choline is an essential nutrient for proper liver, muscle, and brain functions as well as for lipid metabolism and cellular membrane composition and repair. Humans can produce small amounts of choline via the hepatic phosphatidylethanolamine
MeSH term(s)	Choline ; Diet ; Female ; Folic Acid ; Humans ; Maternal Nutritional Physiological Phenomena ; Nutritional Requirements ; Pregnancy ; Vitamins
Chemical Substances	Vitamins ; Folic Acid (935E97BOY8) ; Choline (N91BDP6H0X)
Language	English
Publishing date	2019-08-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2460305-3
ISSN	1939-022X ; 1939-0211
ISSN (online)	1939-022X
ISSN	1939-0211
DOI	10.1080/19390211.2019.1639875
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Article ; Online: Neuroprotective actions of perinatal choline nutrition.

Blusztajn, Jan Krzysztof / Mellott, Tiffany J

Clinical chemistry and laboratory medicine

2013 Volume 51, Issue 3, Page(s) 591–599

Abstract: Choline is an essential nutrient for humans. Studies in rats and mice have shown that high choline intake during gestation or the perinatal period improves cognitive function in adulthood, prevents memory decline of old age, and protects the brain from ... ...

Abstract	Choline is an essential nutrient for humans. Studies in rats and mice have shown that high choline intake during gestation or the perinatal period improves cognitive function in adulthood, prevents memory decline of old age, and protects the brain from damage and cognitive and neurological deterioration associated with epilepsy and hereditary conditions such as Down's and Rett syndromes. These behavioral changes are accompanied by modified patterns of expression of hundreds of cortical and hippocampal genes including those encoding proteins central for learning and memory processing. The effects of choline correlate with cerebral cortical changes in DNA and histone methylation, thus suggesting an epigenomic mechanism of action of perinatal choline.
MeSH term(s)	Animals ; Brain/drug effects ; Brain/metabolism ; Choline/pharmacology ; Choline/therapeutic use ; DNA/metabolism ; Epilepsy/drug therapy ; Gene Expression Regulation ; Hippocampus/drug effects ; Hippocampus/metabolism ; Histones/metabolism ; Humans ; Memory/drug effects ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use
Chemical Substances	Histones ; Neuroprotective Agents ; DNA (9007-49-2) ; Choline (N91BDP6H0X)
Language	English
Publishing date	2013-01-13
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	1418007-8
ISSN	1437-4331 ; 1434-6621 ; 1437-8523
ISSN (online)	1437-4331
ISSN	1434-6621 ; 1437-8523
DOI	10.1515/cclm-2012-0635
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Article ; Online: Choline nutrition programs brain development via DNA and histone methylation.

Blusztajn, Jan Krzysztof / Mellott, Tiffany J

Central nervous system agents in medicinal chemistry

2012 Volume 12, Issue 2, Page(s) 82–94

Abstract: Choline is an essential nutrient for humans. Metabolically choline is used for the synthesis of membrane phospholipids (e.g. phosphatidylcholine), as a precursor of the neurotransmitter acetylcholine, and, following oxidation to betaine, choline ... ...

Abstract	Choline is an essential nutrient for humans. Metabolically choline is used for the synthesis of membrane phospholipids (e.g. phosphatidylcholine), as a precursor of the neurotransmitter acetylcholine, and, following oxidation to betaine, choline functions as a methyl group donor in a pathway that produces S-adenosylmethionine. As a methyl donor choline influences DNA and histone methylation--two central epigenomic processes that regulate gene expression. Because the fetus and neonate have high demands for choline, its dietary intake during pregnancy and lactation is particularly important for normal development of the offspring. Studies in rodents have shown that high choline intake during gestation improves cognitive function in adulthood and prevents memory decline associated with old age. These behavioral changes are accompanied by electrophysiological, neuroanatomical, and neurochemical changes and by altered patterns of expression of multiple cortical and hippocampal genes including those encoding key proteins that contribute to the biochemical mechanisms of learning and memory. These actions of choline are observed long after the exposure to the nutrient ended (months) and correlate with fetal hepatic and cerebral cortical choline-evoked changes in global- and gene-specific DNA cytosine methylation and with dramatic changes of the methylation pattern of lysine residues 4, 9 and 27 of histone H3. Moreover, gestational choline modulates the expression of DNA (Dnmt1, Dnmt3a) and histone (G9a/Ehmt2/Kmt1c, Suv39h1/Kmt1a) methyltransferases. In addition to the central role of DNA and histone methylation in brain development, these processes are highly dynamic in adult brain, modulate the expression of genes critical for synaptic plasticity, and are involved in mechanisms of learning and memory. A recent study documented that in a cohort of normal elderly people, verbal and visual memory function correlated positively with the amount of dietary choline consumption. It will be important to determine if these actions of choline on human cognition are mediated by epigenomic mechanisms or by its influence on acetylcholine or phospholipid synthesis.
MeSH term(s)	Animals ; Brain/drug effects ; Brain/growth & development ; Brain/metabolism ; Choline/administration & dosage ; Choline/metabolism ; Choline Deficiency/diet therapy ; Choline Deficiency/metabolism ; Choline Deficiency/prevention & control ; DNA Methylation/physiology ; Female ; Histones/metabolism ; Humans ; Nutritional Status/physiology ; Pregnancy
Chemical Substances	Histones ; Choline (N91BDP6H0X)
Language	English
Publishing date	2012-03-30
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2227560-5
ISSN	1875-6166 ; 1871-5249
ISSN (online)	1875-6166
ISSN	1871-5249
DOI	10.2174/187152412800792706
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