Mount Sinai ADRC (Sano): Project 2 (Buettner) | PROJECT SUMMARY Potential factors contributing to the increased risk for cognitive impairment (CI) in type 2 diabetes (T2D) include: (a) components of Alzheimer's disease (AD) pathology (plaques, tangles, synapse loss, neuronal loss); (b) atherosclerotic vasculopathy; (c) brain insulin resistance; (d) inflammation; (e) prior episodes of hypoglycemia; (f) other, as yet unknown factors. In the only report of this topic in which AD brain has been assessed directly, Talbot et al 17 presented evidence in support of the hypothesis that insulin resistance is a consistent feature of all typical, sporadic AD. Project 2 focuses on the putative pathophysiological underpinnings between insulin resistance/T2D and CI. Investigators in Project 2 will use an induced pluripotent stem cell (iPSC) strategy to derive neurons, astrocytes, mixed brain cell cultures, and white adipocytes from various clinical populations defined in Project 1. The neurons, astrocytes, and mixed cultures will be used to study the cellular phenotypes and insulin sensitivities of central nervous system (CNS) cells, while the adipocytes will be used as exemplars of peripheral insulin-sensitive cells. We will assess quantitatively the insulin sensitivities in CNS and peripheral cells derived from iPSCs from various clinical populations defined in Project 1. In order to establish the insulin sensitivity of the iPSC-derived neuron, we will study classical insulin signaling pathways in all cell types as assessed through the phosphorylation state of downstream signaling molecules. Importantly, as a physiological readout for insulin action, we will study neurons by electrophysiology and calcium imaging, while adipocytes will be characterized through the assessment of the ability of insulin to increase glucose uptake and to suppress lipolysis. To ascertain the dependence of these responses of insulin signaling through the insulin receptor, we will employ both pharmacological or molecular approaches, the latter via an antisense-mediated knockdown of the insulin receptor or the expression of a dominant-negative mutant version of the insulin-like growth factor (IGF)-1 receptor that heterodimerizes with the insulin receptor and blocks its function. These studies will establish whether insulin resistance is a feature of AD in peripheral and/or brain cells. Additional studies will provide a direct assessment for the possible participation of insulin resistance in the generation of structural pathology causing or predisposing to CI. With regard to pathology, we will measure insulin-stimulated A? secretion, and insulin-modulated tau phosphorylation in brain cells derived from the clinical populations defined in Project 1. Overall, the data derived from this project will test the hypothesis that insulin resistance is a consistent feature of the sporadic AD phenotype.

Public Health Relevance

Mount Sinai ADRC: Project 2 (Buettner) | NARRATIVE Narrative Project 2 will study the link between insulin resistance/type 2 diabetes (T2D) and cognitive impairment using induced pluripotent stem cells (iPSC) from various clinical populations defined in Project 1. These cells will be used to generate brain cells and white adipocytes to test whether central nervous system (CNS) insulin resistance links T2D and AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
5P50AG005138-33
Application #
9280770
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
33
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Sano, Mary; Zhu, Carolyn W; Grossman, Hillel et al. (2017) Longitudinal Cognitive Profiles in Diabetes: Results From the National Alzheimer's Coordinating Center's Uniform Data. J Am Geriatr Soc 65:2198-2204
Tripodis, Yorghos; Alosco, Michael L; Zirogiannis, Nikolaos et al. (2017) The Effect of Traumatic Brain Injury History with Loss of Consciousness on Rate of Cognitive Decline Among Older Adults with Normal Cognition and Alzheimer's Disease Dementia. J Alzheimers Dis 59:251-263
Brenowitz, Willa D; Hubbard, Rebecca A; Keene, C Dirk et al. (2017) Mixed neuropathologies and estimated rates of clinical progression in a large autopsy sample. Alzheimers Dement 13:654-662
Jutkowitz, Eric; Kane, Robert L; Gaugler, Joseph E et al. (2017) Societal and Family Lifetime Cost of Dementia: Implications for Policy. J Am Geriatr Soc 65:2169-2175
Livny, Abigail; Ravona-Springer, Ramit; Heymann, Anthony et al. (2017) Haptoglobin 1-1 Genotype Modulates the Association of Glycemic Control With Hippocampal Volume in Elderly Individuals With Type 2 Diabetes. Diabetes 66:2927-2932
Moheb, Negar; Mendez, Mario F; Kremen, Sarah A et al. (2017) Executive Dysfunction and Behavioral Symptoms Are Associated with Deficits in Instrumental Activities of Daily Living in Frontotemporal Dementia. Dement Geriatr Cogn Disord 43:89-99
Monsell, Sarah E; Mock, Charles; Fardo, David W et al. (2017) Genetic Comparison of Symptomatic and Asymptomatic Persons With Alzheimer Disease Neuropathology. Alzheimer Dis Assoc Disord 31:232-238
Jiang, Yan; Loh, Yong-Hwee Eddie; Rajarajan, Prashanth et al. (2017) The methyltransferase SETDB1 regulates a large neuron-specific topological chromatin domain. Nat Genet 49:1239-1250
Kaur, G; Pawlik, M; Gandy, S E et al. (2017) Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein. Mol Psychiatry 22:981-989
Mez, Jesse; Chung, Jaeyoon; Jun, Gyungah et al. (2017) Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans. Alzheimers Dement 13:119-129

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