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Principal Investigator: HEIDI A TISSENBAUM
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2024
Award: $209,375
Funding agency: National Institute on Aging
Project Summary/Abstract
Our population is aging. As our population ages, the incidence of Alzheimer’s Disease (AD), an
age-associated illness, grows, resulting in elevated health care costs. A second factor contributing
to the current rise in age-associated aliments is the American diet with its ever-increasing amount
of added sugar. The negative effects of added dietary sugar is in part due to advanced glycation
end products (AGEs) which form from the process of glycation where a sugar molecule attaches
to a protein or lipid without enzymatic regulation thereby altering its structure and/or function.
AGEs form in normal metabolism but when AGEs rise to high levels in tissues and circulation, as
in diabetes or high dietary sugar, they can become pathogenic since AGEs promote oxidative
stress and inflammation. A third contributor to the increases in AD is the microbiome; recent
studies have linked age-associated illness with changes in the microbiome. The central unifying
hypothesis of this proposal is that consumption of a sugar-loaded diet alters the microbiome and
contributes to the onset and severity of AD. We will address this hypothesis with two specific aims
using a Caenorhabditis elegans–Escherichia coli system.
Our experimental C. elegans–E. coli paradigm is an excellent system for these studies
because: (1) C. elegans are bacterivores and have an obligatory symbiotic relationship with
microbes as their food source, which becomes the intestinal microbiota; (2) C. elegans possess
stress and immune signaling pathways that are evolutionarily conserved; (3) Genetic tools are
available including transgenic strains for AD whereby human β-Amyloid precursor protein (Aβ
peptide) is driven by a tissue specific promoter. (4) We can modify the environment (added sugar)
resulting in changes in the levels of dietary AGEs(dAGEs); and (5) Our preliminary data show
when C. elegans consume live (microbiota) or heat killed (no microbiota) sugar-loaded high-
dAGE E. coli, C. elegans have a shortened lifespan and reduced healthspan. Our results also
demonstrate the importance of the microbiota as a buffer for stress. In Specific Aim 1, we will
address the effects of a sugar-loaded high-dAGEs diet on AD transgenic animals with heat killed
or live bacteria. In Specific Aim 2, we use a series of genetic tools, (including mutants,
transgenics)to provide mechanistic insight. This proposal exploits a symbiotic relationship to
define how a sugar loaded/high dAGEs diet promotes Aβ accumulation. Our results in the two-
year period could be paradigm shifting in our understanding of the impact of added dietary glucose
on AD. The long-term goal is to modify diet to delay or even eliminate the onset of AD.
Terms: <A β-42><A β42><A-beta 42><A-beta42><AD dementia><Abeta-42><Abeta42><Address><Advanced Glycation End Products><Advanced Glycosylation End Products><Affect><Ag element><Age><Aging><Ailmentary System><Alimentary System><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease patient><Alzheimer's patient><Alzheimers Dementia><American><American diet><Amino Acids><Amyloid A4 Protein Precursor><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid Protein Precursor><Amyloid beta-42><Amyloid beta-Protein><Amyloid beta-Protein Precursor><Amyloid beta42><Amyloid β><Amyloid β-42><Amyloid β-Peptide><Amyloid β-Protein><Amyloid β-Protein Precursor><Amyloid β42><Amyloidβ-42><Amyloidβ42><Animal Diseases><Animals><Aβ><Aβ-42><Aβ42><Bacteria><Body Tissues><Brain><Brain Nervous System><Buffers><C elegans><C. elegans><C.elegans><Caenorhabditis elegans><Circulation><Consumption><D-Glucose><Data><Dextrose><Diabetes Mellitus><Diet><Dietary Sugars><Digestive System><E coli><E. coli><Economics><Encephalon><Environment><Escherichia coli><Food><GI microbiota><Gastrointestinal Body System><Gastrointestinal Organ System><Gastrointestinal microbiota><Genes><Genetic><Glucose><Goals><Grant><Health><Health Care Costs><Health Costs><Healthcare Costs><Human><Immune><Immune signaling><Immunes><Incidence><Inflammation><Intermediary Metabolism><Intervention><Intervention Strategies><Link><Lipids><Metabolic Processes><Metabolism><Microbe><Modern Man><Movement><Muscle><Muscle Tissue><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Ortholog><Orthologous Gene><Oxidative Stress><Palsy><Paralysed><Pathogenicity><Pathway interactions><Peptides><Persons><Plegia><Population><Primary Senile Degenerative Dementia><Process><Proteins><Publishing><Regulation><Series><Severities><Signal Pathway><Silver><Source><Stress><Structure><System><Testing><Tissues><Transgenic Animals><Transgenic Organisms><Tsunami><a beta peptide><abeta><abeta accumulation><abeta aggregation><advanced glycation endproduct><advanced glycosylation endproduct><age associated><age correlated><age dependent><age linked><age related><age specific><ages><alter microbiome><aminoacid><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid precursor protein><amyloid β accumulation><amyloid β aggregation><amyloid-b protein><aβ accumulation><aβ aggregation><beta amyloid fibril><body movement><constitutive expression><constitutive gene expression><diabetes><dietary><diets><economic><enteric microbial community><enteric microbiota><gastrointestinal microbial flora><gastrointestinal system><glycation><gut commensal><gut community><gut flora><gut microbe community><gut microbial community><gut microbial composition><gut microbial consortia><gut microbiota><gut microbiotic><gut microflora><health-span><healthspan><healthy life span><inducible expression><inducible gene expression><insight><interventional strategy><intestinal flora><intestinal microbiota><intestinal microflora><intestinal tract microflora><life span><lifespan><microbial consortia><microbial flora><microbiome><microbiome adaptation><microbiome alteration><microbiome perturbation><microbiota><microflora><multispecies consortia><muscular><mutant><neuronal><non-enzymatic glycosylation><nonenzymatic glycosylation><paralysis><paralytic><pathway><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><presenilin><primary degenerative dementia><promoter><promotor><senile dementia of the Alzheimer type><social stress><socially stressed><soluble amyloid precursor protein><stress buffering><stress management><sugar><tool><transgenic>