Diet-induced Alzheimer's-like syndrome in the rabbit

Craig Weiss; Nicola Bertolino; Daniele Procissi; Grazia Aleppo; Quinn C. Smith; Kirsten L. Viola; Samuel C. Bartley; William L. Klein; John F. Disterhoft

doi:10.1002/trc2.12241

Diet-induced Alzheimer's-like syndrome in the rabbit

Craig Weiss^*, Nicola Bertolino, Daniele Procissi, Grazia Aleppo, Quinn C. Smith, Kirsten L. Viola, Samuel C. Bartley, William L. Klein, John F. Disterhoft

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Introduction: Although mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late-onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild-type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3-like isoform of apolipoprotein. We report a combined behavioral, imaging, and metabolic study using rabbit as a non-transgenic model to examine effects of AD-related risk factors on cognition, intrinsic functional connectivity, and magnetic resonance-based biomarkers of neuropathology. Methods: Aging rabbits were fed a diet enriched with either 2% cholesterol or 10% fat/30% fructose. Monthly tests of novel object recognition (NOR) and object location memory (OLM) were administered to track cognitive impairment. Trace eyeblink conditioning (EBC) was administered as a final test of cognitive impairment. Magnetic resonance imaging (MRI) was used to obtain resting state connectivity and quantitative parametric data (R₂*). Results: Experimental diets induced hypercholesterolemia or elevated BGL. Both experimental diets induced statistically significant impairment of OLM (but not NOR) and altered intrinsic functional connectivity. EBC was more impaired by fat/fructose diet than by cholesterol. Whole brain and regional R₂* MRI values were elevated in both experimental diet groups relative to rabbits on the control diet. Discussion: We propose that mechanisms underlying LOAD can be assessed by stressing risk factors for inducing AD and that dietary manipulations can be used to assess etiological differences in the pathologies and effectiveness of potential therapeutics against LOAD. In addition, non-invasive MRI in awake, non-anesthetized rabbits further increases the translational value of this non-transgenic model to study AD.

Original language	English (US)
Article number	e12241
Journal	Alzheimer's and Dementia: Translational Research and Clinical Interventions
Volume	8
Issue number	1
DOIs	https://doi.org/10.1002/trc2.12241
State	Published - 2022

Funding

Grazia Aleppo is partially supported by Novo‐Nordisk, Eli‐Lilly, and Insulet/Dexcom. Payments to William L. Klein were made to organize a meeting for Acumen Pharmaceuticals. William L. Klein has founders’ shares in Acumen Pharmaceuticals and is a member of the scientific advisory board of Acumen. ACU193 was a gift from Acumen Pharmaceuticals. NU2 was developed with support from NIH Grants RO1AG18877 and RO1AG22547 to Northwestern University. Support paid to Northwestern University from NIH R01 AG063903, NIH‐R21 AG060203‐01, NIH‐R43OD023025‐01A1 (subcontract from Virscio, Inc). Imaging partially supported by the Rice Foundation. John F. Disterhoft supported by NIH R01 NS113804, R01 MH114923, R25 GM121231, T32 AG20506‐16‐20, RF1 AG017139, R37 AG008796‐28S1, R21 AG060267. John F. Disterhoft received payment from Brain Research Foundation for grant review service, and received payment from International Bordeaux Neurocampus Aging Meeting (2018). John F. Disterhoft is an unpaid member of Chicago Methodist Senior Services Board. Craig Weiss, Nicola Bertolino, Daniele Procissi, Quinn C. Smith, Kirsten L. Viola, Samuel C. Bartley have no disclosures. We thank Nicholas Rozema and Mary Kando for help with rabbit behavioral studies. Microscopy was performed at the Biological Imaging Facility at Northwestern University ( RRID:SCR_017767 ), graciously supported by the Chemistry for Life Processes Institute, the NU Office for Research, and the Department of Molecular Biosciences and the Rice Foundation. Funded in part by: National Institutes of Health R56 AG050492, R01 NS113804, UL1TR001422, AG013854. Eleanor Wood Prince Grant from the Woman's Board of Northwestern Memorial Hospital.

Keywords

cholesterol
diabetes
eyeblink conditioning
late onset Alzheimer's disease
magnetic resonance imaging
whole-brain R*

ASJC Scopus subject areas

Clinical Neurology
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/trc2.12241

Cite this

@article{b607c3128f794b2eb13ad319876956df,

title = "Diet-induced Alzheimer's-like syndrome in the rabbit",

abstract = "Introduction: Although mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late-onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild-type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3-like isoform of apolipoprotein. We report a combined behavioral, imaging, and metabolic study using rabbit as a non-transgenic model to examine effects of AD-related risk factors on cognition, intrinsic functional connectivity, and magnetic resonance-based biomarkers of neuropathology. Methods: Aging rabbits were fed a diet enriched with either 2% cholesterol or 10% fat/30% fructose. Monthly tests of novel object recognition (NOR) and object location memory (OLM) were administered to track cognitive impairment. Trace eyeblink conditioning (EBC) was administered as a final test of cognitive impairment. Magnetic resonance imaging (MRI) was used to obtain resting state connectivity and quantitative parametric data (R2*). Results: Experimental diets induced hypercholesterolemia or elevated BGL. Both experimental diets induced statistically significant impairment of OLM (but not NOR) and altered intrinsic functional connectivity. EBC was more impaired by fat/fructose diet than by cholesterol. Whole brain and regional R2* MRI values were elevated in both experimental diet groups relative to rabbits on the control diet. Discussion: We propose that mechanisms underlying LOAD can be assessed by stressing risk factors for inducing AD and that dietary manipulations can be used to assess etiological differences in the pathologies and effectiveness of potential therapeutics against LOAD. In addition, non-invasive MRI in awake, non-anesthetized rabbits further increases the translational value of this non-transgenic model to study AD.",

keywords = "cholesterol, diabetes, eyeblink conditioning, late onset Alzheimer's disease, magnetic resonance imaging, whole-brain R*",

author = "Craig Weiss and Nicola Bertolino and Daniele Procissi and Grazia Aleppo and Smith, {Quinn C.} and Viola, {Kirsten L.} and Bartley, {Samuel C.} and Klein, {William L.} and Disterhoft, {John F.}",

note = "Funding Information: Grazia Aleppo is partially supported by Novo‐Nordisk, Eli‐Lilly, and Insulet/Dexcom. Payments to William L. Klein were made to organize a meeting for Acumen Pharmaceuticals. William L. Klein has founders{\textquoteright} shares in Acumen Pharmaceuticals and is a member of the scientific advisory board of Acumen. ACU193 was a gift from Acumen Pharmaceuticals. NU2 was developed with support from NIH Grants RO1AG18877 and RO1AG22547 to Northwestern University. Support paid to Northwestern University from NIH R01 AG063903, NIH‐R21 AG060203‐01, NIH‐R43OD023025‐01A1 (subcontract from Virscio, Inc). Imaging partially supported by the Rice Foundation. John F. Disterhoft supported by NIH R01 NS113804, R01 MH114923, R25 GM121231, T32 AG20506‐16‐20, RF1 AG017139, R37 AG008796‐28S1, R21 AG060267. John F. Disterhoft received payment from Brain Research Foundation for grant review service, and received payment from International Bordeaux Neurocampus Aging Meeting (2018). John F. Disterhoft is an unpaid member of Chicago Methodist Senior Services Board. Craig Weiss, Nicola Bertolino, Daniele Procissi, Quinn C. Smith, Kirsten L. Viola, Samuel C. Bartley have no disclosures. Funding Information: We thank Nicholas Rozema and Mary Kando for help with rabbit behavioral studies. Microscopy was performed at the Biological Imaging Facility at Northwestern University ( RRID:SCR_017767 ), graciously supported by the Chemistry for Life Processes Institute, the NU Office for Research, and the Department of Molecular Biosciences and the Rice Foundation. Funded in part by: National Institutes of Health R56 AG050492, R01 NS113804, UL1TR001422, AG013854. Eleanor Wood Prince Grant from the Woman's Board of Northwestern Memorial Hospital. Publisher Copyright: {\textcopyright} 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.",

year = "2022",

doi = "10.1002/trc2.12241",

language = "English (US)",

volume = "8",

journal = "Alzheimer's and Dementia: Translational Research and Clinical Interventions",

issn = "2352-8737",

publisher = "John Wiley and Sons Inc.",

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TY - JOUR

T1 - Diet-induced Alzheimer's-like syndrome in the rabbit

AU - Weiss, Craig

AU - Bertolino, Nicola

AU - Procissi, Daniele

AU - Aleppo, Grazia

AU - Smith, Quinn C.

AU - Viola, Kirsten L.

AU - Bartley, Samuel C.

AU - Klein, William L.

AU - Disterhoft, John F.

N1 - Funding Information: Grazia Aleppo is partially supported by Novo‐Nordisk, Eli‐Lilly, and Insulet/Dexcom. Payments to William L. Klein were made to organize a meeting for Acumen Pharmaceuticals. William L. Klein has founders’ shares in Acumen Pharmaceuticals and is a member of the scientific advisory board of Acumen. ACU193 was a gift from Acumen Pharmaceuticals. NU2 was developed with support from NIH Grants RO1AG18877 and RO1AG22547 to Northwestern University. Support paid to Northwestern University from NIH R01 AG063903, NIH‐R21 AG060203‐01, NIH‐R43OD023025‐01A1 (subcontract from Virscio, Inc). Imaging partially supported by the Rice Foundation. John F. Disterhoft supported by NIH R01 NS113804, R01 MH114923, R25 GM121231, T32 AG20506‐16‐20, RF1 AG017139, R37 AG008796‐28S1, R21 AG060267. John F. Disterhoft received payment from Brain Research Foundation for grant review service, and received payment from International Bordeaux Neurocampus Aging Meeting (2018). John F. Disterhoft is an unpaid member of Chicago Methodist Senior Services Board. Craig Weiss, Nicola Bertolino, Daniele Procissi, Quinn C. Smith, Kirsten L. Viola, Samuel C. Bartley have no disclosures. Funding Information: We thank Nicholas Rozema and Mary Kando for help with rabbit behavioral studies. Microscopy was performed at the Biological Imaging Facility at Northwestern University ( RRID:SCR_017767 ), graciously supported by the Chemistry for Life Processes Institute, the NU Office for Research, and the Department of Molecular Biosciences and the Rice Foundation. Funded in part by: National Institutes of Health R56 AG050492, R01 NS113804, UL1TR001422, AG013854. Eleanor Wood Prince Grant from the Woman's Board of Northwestern Memorial Hospital. Publisher Copyright: © 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.

PY - 2022

Y1 - 2022

N2 - Introduction: Although mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late-onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild-type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3-like isoform of apolipoprotein. We report a combined behavioral, imaging, and metabolic study using rabbit as a non-transgenic model to examine effects of AD-related risk factors on cognition, intrinsic functional connectivity, and magnetic resonance-based biomarkers of neuropathology. Methods: Aging rabbits were fed a diet enriched with either 2% cholesterol or 10% fat/30% fructose. Monthly tests of novel object recognition (NOR) and object location memory (OLM) were administered to track cognitive impairment. Trace eyeblink conditioning (EBC) was administered as a final test of cognitive impairment. Magnetic resonance imaging (MRI) was used to obtain resting state connectivity and quantitative parametric data (R2*). Results: Experimental diets induced hypercholesterolemia or elevated BGL. Both experimental diets induced statistically significant impairment of OLM (but not NOR) and altered intrinsic functional connectivity. EBC was more impaired by fat/fructose diet than by cholesterol. Whole brain and regional R2* MRI values were elevated in both experimental diet groups relative to rabbits on the control diet. Discussion: We propose that mechanisms underlying LOAD can be assessed by stressing risk factors for inducing AD and that dietary manipulations can be used to assess etiological differences in the pathologies and effectiveness of potential therapeutics against LOAD. In addition, non-invasive MRI in awake, non-anesthetized rabbits further increases the translational value of this non-transgenic model to study AD.

AB - Introduction: Although mouse models of Alzheimer's disease (AD) have increased our understanding of the molecular basis of the disease, none of those models represent late-onset Alzheimer's Disease which accounts for >90% of AD cases, and no therapeutics developed in the mouse (with the possible exceptions of aduhelm/aducanumab and gantenerumab) have succeeded in preventing or reversing the disease. This technology has allowed much progress in understanding the molecular basis of AD. To further enhance our understanding, we used wild-type rabbit (with a nearly identical amino acid sequence for amyloid as in humans) to model LOAD by stressing risk factors including age, hypercholesterolemia, and elevated blood glucose levels (BGLs), upon an ε3-like isoform of apolipoprotein. We report a combined behavioral, imaging, and metabolic study using rabbit as a non-transgenic model to examine effects of AD-related risk factors on cognition, intrinsic functional connectivity, and magnetic resonance-based biomarkers of neuropathology. Methods: Aging rabbits were fed a diet enriched with either 2% cholesterol or 10% fat/30% fructose. Monthly tests of novel object recognition (NOR) and object location memory (OLM) were administered to track cognitive impairment. Trace eyeblink conditioning (EBC) was administered as a final test of cognitive impairment. Magnetic resonance imaging (MRI) was used to obtain resting state connectivity and quantitative parametric data (R2*). Results: Experimental diets induced hypercholesterolemia or elevated BGL. Both experimental diets induced statistically significant impairment of OLM (but not NOR) and altered intrinsic functional connectivity. EBC was more impaired by fat/fructose diet than by cholesterol. Whole brain and regional R2* MRI values were elevated in both experimental diet groups relative to rabbits on the control diet. Discussion: We propose that mechanisms underlying LOAD can be assessed by stressing risk factors for inducing AD and that dietary manipulations can be used to assess etiological differences in the pathologies and effectiveness of potential therapeutics against LOAD. In addition, non-invasive MRI in awake, non-anesthetized rabbits further increases the translational value of this non-transgenic model to study AD.

KW - cholesterol

KW - diabetes

KW - eyeblink conditioning

KW - late onset Alzheimer's disease

KW - magnetic resonance imaging

KW - whole-brain R

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Diet-induced Alzheimer's-like syndrome in the rabbit

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ASJC Scopus subject areas

UN SDGs

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