Summary of Study ST003215

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002005. The data can be accessed directly via it's Project DOI: 10.21228/M8FJ9V This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST003215
Study TitleProtein restriction slows the development and progression of Alzheimer's disease in mice
Study SummaryDietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and many independent groups of researchers have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer’s disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice and rescuing the glucose intolerance of 3xTg females. We found that PR induces sex-specific alterations in circulating metabolites and in the brain lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.
Institute
University of Wisconsin-Madison
Last NameSimcox
First NameJudith
Address433 Babcock Dr, Madison, WI, 53706, USA
Emailjsimcox@wisc.edu
Phone-
Submit Date2024-05-20
Total Subjects40
Num Males20
Num Females20
Raw Data AvailableYes
Raw Data File Type(s)mzdata.xml
Analysis Type DetailLC-MS
Release Date2024-06-12
Release Version1
Judith Simcox Judith Simcox
https://dx.doi.org/10.21228/M8FJ9V
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR002005
Project DOI:doi: 10.21228/M8FJ9V
Project Title:Protein restriction slows the development and progression of Alzheimer's disease in mice
Project Type:MS targeted lipidomics
Project Summary:Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and many independent groups of researchers have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer’s disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice and rescuing the glucose intolerance of 3xTg females. We found that PR induces sex-specific alterations in circulating metabolites and in the brain lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.
Institute:University of Wisconsin-Madison
Last Name:Simcox
First Name:Judith
Address:433 Babcock Dr, Madison, WI, 53706, USA
Email:jsimcox@wisc.edu
Phone:-

Subject:

Subject ID:SU003334
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Genotype Strain:3xTg
Gender:Male and female
Animal Feed:Control, TD.180161; PR, TD.10192

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Sample source Genotype Treatment
SA351738F13Brain 3xTg Control
SA351739F11Brain 3xTg Control
SA351740F14Brain 3xTg Control
SA351741M12Brain 3xTg Control
SA351742M11Brain 3xTg Control
SA351743M13Brain 3xTg Control
SA351744F15Brain 3xTg Control
SA351745F12Brain 3xTg Control
SA351746M14Brain 3xTg Control
SA351747M15Brain 3xTg Control
SA351748F19Brain 3xTg Protein restriction
SA351749F20Brain 3xTg Protein restriction
SA351750M19Brain 3xTg Protein restriction
SA351751M20Brain 3xTg Protein restriction
SA351752F18Brain 3xTg Protein restriction
SA351753F16Brain 3xTg Protein restriction
SA351754M16Brain 3xTg Protein restriction
SA351755F17Brain 3xTg Protein restriction
SA351756M17Brain 3xTg Protein restriction
SA351757M18Brain 3xTg Protein restriction
SA351758M5Brain Non-transgenic Control
SA351759M4Brain Non-transgenic Control
SA351760M1Brain Non-transgenic Control
SA351761F1Brain Non-transgenic Control
SA351762M3Brain Non-transgenic Control
SA351763M2Brain Non-transgenic Control
SA351764F5Brain Non-transgenic Control
SA351765F2Brain Non-transgenic Control
SA351766F3Brain Non-transgenic Control
SA351767F4Brain Non-transgenic Control
SA351768F7Brain Non-transgenic Protein restriction
SA351769F6Brain Non-transgenic Protein restriction
SA351770F8Brain Non-transgenic Protein restriction
SA351771F10Brain Non-transgenic Protein restriction
SA351772M7Brain Non-transgenic Protein restriction
SA351773M6Brain Non-transgenic Protein restriction
SA351774M8Brain Non-transgenic Protein restriction
SA351775M9Brain Non-transgenic Protein restriction
SA351776M10Brain Non-transgenic Protein restriction
SA351777F9Brain Non-transgenic Protein restriction
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Collection:

Collection ID:CO003327
Collection Summary:Mice were euthanized by cervical dislocation after a 3 hour fast, and the right hemisphere was fixed in formalin for histology whereas the left hemisphere was snap-frozen for mass spectrometry analysis.
Sample Type:Brain

Treatment:

Treatment ID:TR003343
Treatment Summary:At the start of the experiment, mice were randomized to receive either a 21% protein diet (Control, TD.180161) or a 7% protein diet (PR, TD.10192) obtained from Envigo. Our diets were formulated to be isocaloric, meaning that any reduction in protein content was compensated for by adjusting the carbohydrate content and fat percent stayed constant.

Sample Preparation:

Sampleprep ID:SP003341
Sampleprep Summary:Whole brain samples were pulverized and 20 mg were homogenized in 215 µL MeOH plus 10 µL of a 30 µM solution of each of the following internal standards: Cer d18:1(d7)_15:0 (Avanti #67492-15-3), Cer d18:1(d7)_16:0 (Avanti # 1840942-13-3), Cer d18:1(d7)_18:0 (Avanti #1840942-14-4), Cer d18:1(d7)_24:0 (Avanti #1840942-15-5), Cer d18:1(d7)_24:1 (Avanti # 1840942-16-6), and SM d18:1(d7)_18:1 (Avanti # 2342574-42-7). The samples were homogenized in bead tubes (1.4mm, Qiagen, #13113-50) in a Qiagen TissueLyzer II (catalog no.: 9244420) for 2 cycles in blocks chilled to 4°C. 250 µL H2O and 750 µL MTBE were then added, and the samples were inverted to mix and placed on ice. After 15 minutes, the samples were centrifuged at 4 °C at 16000 x g for 5 minutes, and 500 µL of the top organic phase was removed into a new tube and dried using a speedvac. Lipids were then resuspended in 150 µL IPA and stored at -20°C until analysis. An insoluble precipitate was also observed when the extracts were resuspended in IPA.

Combined analysis:

Analysis ID AN005272
Analysis type MS
Chromatography type Reversed phase
Chromatography system Agilent 1290 Infinity II
Column Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um)
MS Type ESI
MS instrument type Triple quadrupole
MS instrument name Agilent 6495 QQQ
Ion Mode POSITIVE
Units ng lipid/mg brain

Chromatography:

Chromatography ID:CH003989
Chromatography Summary:For targeted sphingolipid separation
Instrument Name:Agilent 1290 Infinity II
Column Name:Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um)
Column Temperature:60
Flow Gradient:The gradient began with 30% B and increased to 60% over 1.8 min, then increased to 80% until 7 min and 99% until 7.14 min, which was maintained until 10 min.
Flow Rate:0.5 mL/min
Solvent A:60:40 acetonitrile:water; 10 mM ammonium formate; 0.1% formic acid
Solvent B:9:1:90 acetonitrile:water:isopropyl alcolhol; 10 mM ammonium formate; 0.1% formic acid
Chromatography Type:Reversed phase

MS:

MS ID:MS005003
Analysis ID:AN005272
Instrument Name:Agilent 6495 QQQ
Instrument Type:Triple quadrupole
MS Type:ESI
MS Comments:Data was processed in the Agilent MassHunter Wokstation, and sphingolipids were quantified by peak height based on the relative concentration of the appropriate internal standard within the samples.
Ion Mode:POSITIVE
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