Aging and chronic hyperglycemia results in several metabolic and biochemical perturbations including elevation of a series of highly reactive ?-dicarbonyl compounds (?-DCs, e.g., Methylglyoxal(MGO). ?-DCs are unavoidable byproducts largely of anaerobic glycolysis which react indiscriminately with proteins, lipids, and DNA to yield a heterogeneous group of molecules called advanced glycation end products (AGEs). A large body of evidence has linked accelerated glucose metabolism and diabetes to neurodegenerative diseases like Alzheimer's disease (AD). We hypothesize that toxic byproducts of glucose metabolism that result in the formation of AGEs explain the enhanced risk of AD due to hyperglycemia and diabetes. In support of this AGEs in serum and AGE crosslinking in protein aggregates have been associated with enhanced neurodegeneration in AD. However, AGEs are hard to model as they take years to accumulate in humans and the mechanism by which they cause cellular damage remains to be elucidated. To overcome this gap, we have established C. elegans (worm) models that significantly accumulate ?-DCs and AGEs, exhibiting several age- related pathologies, such as hypersensitivity to touch, neuronal damage, paralysis, and early mortality, all within three weeks of adulthood. In addition, we have observed that direct administration of synthetic methylglyoxal derived AGEs can directly cause neurotoxicity. Furthermore, we have observed that a C. elegans model overexpressing the pro-aggregating form of tau, that has been implicated in Alzheimer's disease, is sensitive to feeding either glucose or AGEs in the diet. In this proposal, we will test the hypothesis that changes in glucose and lipid metabolism pathways, especially with age, influence MGO and associated AGEs thereby causing neurodegeneration associated with AD. We will also determine the mechanisms by which AGEs influence metabolic dysfunction and contribute to neurodegeneration in AD.
In Aim 1 we will explore a causal role for the effects of AGEs on neurodegeneration in normal aging and in Alzheimer's disease models using synthetically derived AGEs. We will also examine the role of age-associated changes in glucose metabolism in influencing the levels of MGO and AGEs and enhancing neurodegeneration in models of AD.
In Aim 2 we will determine the relationship between lipid metabolism and production of AGEs. We will genetically and pharmacologically manipulate fatty acid oxidation pathways to examine their influence on modulating neurodegeneration in normal aging and AD models through modulation of AGEs.
In Aim 3 we propose to identify the mechanisms by which AGEs mediate their toxicity leading to inhibition of fatty acid oxidation and neurodegeneration. We will identify AGE-binding proteins and therapeutic targets to modulate AGE-related neurodegeneration. These studies will identify several genetic and pharmacological targets to ameliorate AGEs and slow down the progression of neurodegeneration in AD.

Public Health Relevance

Advanced Glycation End-products (AGEs) are by-products of various metabolic reactions especially glycolysis, that are known to accumulate with age enhancing the risk of diabetic pathologies and Alzheimer?s disease (AD). We will use Caenorhabditis elegans to dissect the conserved metabolic pathways that influence the production and detoxification of AGEs and how they modulate toxicity in models of Alzheimer disease. This work will identify therapeutic targets that influence neurodegeneration by mitigating the influence of AGEs during aging and in Alzheimer disease models.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG061165-02
Application #
10017128
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wise, Bradley C
Project Start
2019-09-15
Project End
2024-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945