Hypercholesterolemia causes psychomotor abnormalities in mice and alterations in cortico-striatal biogenic amine neurotransmitters: Relevance to Parkinson's disease

Paul, Rajib; Choudhury, Amarendranath; Boruah, Dulal Chandra; Devi, Rajlakshmi; Bhattacharya, Pallab; Choudhury, Manabendra Dutta; Borah, Anupom

doi:10.1016/j.neuint.2017.01.021

Cited by 34 publications

(28 citation statements)

References 67 publications

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“…To induce hypercholesterolemia, mice were provided with high-cholesterol diet (HCD; 5% w/w cholesterol mixed with normal rodent chow) for 12 weeks ad libitum , which was established in our laboratory 31 . Mice were randomly divided into two groups based on their diets, such as control (provided normal diet) and HCD.…”

Section: Methodsmentioning

confidence: 99%

“…Blood was collected by cardiac-puncture and serum was separated for estimation of cholesterol. Cholesterol was assayed by the enzymatic method using a colorimetric kit following the manufacturer’s instructions (CHOL, Autopak, Siemens) 31 .…”

Section: Methodsmentioning

confidence: 99%

“…Twenty micron thick coronal sections passing through the cortex, striatum, hippocampus and midbrain (mainly substantia nigra) regions of brain were made using Cryostat (0620E, Thermo Shandon, UK). Sections were collected on poly-L-lysine coated slides for histoenzymological studies and in well-plates containing PBS for immunohistological study 31 , 34 .…”

Section: Methodsmentioning

confidence: 99%

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Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice

Paul

Borah

2017

Sci Rep

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There exists an intricate relationship between hypercholesterolemia (elevated plasma cholesterol) and brain functions. The present study aims to understand the impact of hypercholesterolemia on pathological consequences in mouse brain. A chronic mouse model of hypercholesterolemia was induced by giving high-cholesterol diet for 12 weeks. The hypercholesterolemic mice developed cognitive impairment as evident from object recognition memory test. Cholesterol accumulation was observed in four discrete brain regions, such as cortex, striatum, hippocampus and substantia nigra along with significantly damaged blood-brain barrier by hypercholesterolemia. The crucial finding is the loss of acetylcholinesterase activity with mitochondrial dysfunction globally in the brain of hypercholesterolemic mice, which is related to the levels of cholesterol. Moreover, the levels of hydroxyl radical were elevated in the regions of brain where the activity of mitochondrial complexes was found to be reduced. Intriguingly, elevations of inflammatory stress markers in the cholesterol-rich brain regions were observed. As cognitive impairment, diminished brain acetylcholinesterase activity, mitochondrial dysfunctions, and inflammation are the prima facie pathologies of neurodegenerative diseases, the findings impose hypercholesterolemia as potential risk factor towards brain dysfunction.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice

Paul

Borah

2017

Sci Rep

Self Cite

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“…Nevertheless, changes in brain cholesterol have been implicated in numerous neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, and Niemann-Pick disease 44 . For example, hypercholesterolemia causes impairment of dopamine signaling and psychomotor dysfunction in mice [45][46][47][48] . Increases in cholesterol levels have been shown to elevate beta-amyloid precursor protein levels in cholesterol-enriched lipid rafts 49 and are associated with increased risk for AD 50 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis of GIRK2 channel modulation by cholesterol and PIP₂

Mathiharan

Glaaser

Zhao

et al. 2020

Preprint

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Significance/Impact:• GIRK2 is one of the primary GIRK channels in brain. Characterization of cholesterol binding in GIRK2 provides new therapeutic sites for modulating these channels.• Many ion channels are modulated by cholesterol, but the molecular basis of this modulation has been elusive.• First cryoEM structures of pore-forming Kir alpha subunit. Word counts: Abstract (136) -Main text (3048)ABSTRACT G protein-gated inwardly rectifying potassium (GIRK) channels play important roles in controlling cellular excitability in the heart and brain. While structural data begin to unravel the molecular basis for G protein and alcohol dependent activation of GIRK channels, little is known about the modulation by cholesterol. Here, we present cryo-electron microscopy (cryoEM) structures of GIRK2 in the presence and absence of the cholesterol analog cholesteryl hemisuccinate (CHS), and PIP 2 . The structures and their comparison reveal that CHS binds near PIP 2 in lipid-facing hydrophobic pockets of the transmembrane domain (TMD). CHS potentiates the effects of PIP 2 , which stabilizes the inter-domain region and promotes the engagement of the cytoplasmic domain (CTD) onto the transmembrane region. The results suggest that CHS acts as a positive allosteric modulator and identify novel therapeutic sites for modulating GIRK channels in the brain.* is shown with a dashed square.

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“…However, results from experimental studies diverge from epidemiological evidence. Indeed, the induction of serum hypercholesterolemia worsened the phenotype in a PD animal model [ 203 ], while in WT mice it led to dopaminergic loss and motor behavioral abnormalities reminiscent of PD [ 204 ]. Thus, further research is needed to clarify the role of cholesterol in PD.…”

Section: Roles Of Diet and Microbiota In Neurodegenerative Diseasementioning

confidence: 99%

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration

Gentile

Doneddu

Riva

et al. 2020

IJMS

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Increasing evidence gives support for the idea that extra-neuronal factors may affect brain physiology and its predisposition to neurodegenerative diseases. Epidemiological and experimental studies show that nutrition and metabolic disorders such as obesity and type 2 diabetes increase the risk of Alzheimer’s and Parkinson’s diseases after midlife, while the relationship with amyotrophic lateral sclerosis is uncertain, but suggests a protective effect of features of metabolic syndrome. The microbiota has recently emerged as a novel factor engaging strong interactions with neurons and glia, deeply affecting their function and behavior in these diseases. In particular, recent evidence suggested that gut microbes are involved in the seeding of prion-like proteins and their spreading to the central nervous system. Here, we present a comprehensive review of the impact of metabolism, diet and microbiota in neurodegeneration, by affecting simultaneously several aspects of health regarding energy metabolism, immune system and neuronal function. Advancing technologies may allow researchers in the future to improve investigations in these fields, allowing the buildup of population-based preventive interventions and development of targeted therapeutics to halt progressive neurologic disability.

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Hypercholesterolemia causes psychomotor abnormalities in mice and alterations in cortico-striatal biogenic amine neurotransmitters: Relevance to Parkinson's disease

Cited by 34 publications

References 67 publications

Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice

Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice

Structural basis of GIRK2 channel modulation by cholesterol and PIP₂

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration

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Hypercholesterolemia causes psychomotor abnormalities in mice and alterations in cortico-striatal biogenic amine neurotransmitters: Relevance to Parkinson's disease

Cited by 34 publications

References 67 publications

Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice

Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice

Structural basis of GIRK2 channel modulation by cholesterol and PIP2

Diet, Microbiota and Brain Health: Unraveling the Network Intersecting Metabolism and Neurodegeneration

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Structural basis of GIRK2 channel modulation by cholesterol and PIP₂