The systemic diseases, metabolic syndrome (MetS) and Type 2 diabetes mellitus (T2DM), increase risk for Alzheimer's disease (AD). The molecular mechanism for this association remains poorly defined. Here, in preliminary studies we show in human and rodent tissues that elevated glucose, as found in MetS/T2DM, and oligomeric ?-amyloid (A?) peptide, thought to be a key mediator of AD, coordinately increase neuronal Ca2+ and nitric oxide (NO) in an NMDA receptor-dependent fashion. The increase in NO results in nitrosative stress and consequent S-nitrosylation of insulin-degrading enzyme (IDE) and dynamin-related protein 1 (Drp1), thus inhibiting insulin and A? catabolism as well as hyperactivating mitochondrial fission machinery. Consequent elevation in A? levels and compromise in mitochondrial bioenergetics result in dysfunctional synaptic plasticity and synapse loss in cortical and hippocampal neurons. The NMDA receptor antagonist memantine attenuates these effects to some degree, and we posit that the new, improved NMDA receptor antagonist, NitroMemantine, will manifest an even greater beneficial effect. Our preliminary studies show that the redox-mediated posttranslational modification of S-nitrosylation affects brain protein function, thus linking A? and hyperglycemia to cognitive dysfunction in MetS/T2DM and AD. We propose novel studies that do not merely extend our prior findings but instead offer innovative insights by determining a comprehensive compendium of the S-nitrosoproteome and its pathological downstream effects in these diseases. Accordingly, our Specific Aims are as follows:
Aim 1 : To characterize the aberrant S-nitrosoproteome in rat cerebrocortical neuronal cultures, cortico- hippocampal slices, and in hiPSC-derived neurons in in vitro models of Alzheimer?s disease (AD) and type 2 diabetes mellitus (T2DM)/metabolic syndrome (MetS).
Aim 2 : To determine in vivo if brains of db/db (leptin receptor-deficient) mice, as a model of T2DM/MetS, when crossed with J20-hAPP (human amyloid precursor protein overexpressing) AD transgenic (tg) mice, manifest more synaptic and neuronal damage than either mouse model alone. High fat/high glucose fed (to induce the T2DM/MetS phenotype) AD tg mice will also be tested in this manner.
Aim 3 : To determine (a) if treatment with NitroMemantine protects from synaptic and neuronal damage in T2DM/AD genetic mouse models to a greater degree than memantine; and (b) if non-nitrosylatable mutant knockin mice for IDE, Drp1 or new targets are protected from T2DM/AD-mediated synaptic injury.

Public Health Relevance

Alzheimer?s disease (AD) is the most prevalent neurodegenerative disease and represents a major burden on our socio-economic well-being because of the immense cost of nursing home care for our aging population of baby boomers as they develop AD. Another major problem in the aging population is obesity, which is a major predisposing factor for type 2 diabetes mellitus/metabolic syndrome (T2DM/MetS). Epidemiological studies have shown a strong association between the risk of developing T2DM and AD. Here, we demonstrate that an altered chemical redox state due to nitrosative stress contributes to the association of these diseases, and, on this basis, we develop novel therapies to combat these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
1RF1AG057409-01
Application #
9417574
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Petanceska, Suzana
Project Start
2017-09-15
Project End
2022-04-30
Budget Start
2017-09-15
Budget End
2022-04-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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