Mitochondrial dysfunction and synaptic damage are early features of Alzheimer's disease (AD)-6- 10 and diabetes-affected brains. Diabetes negatively affects the brain, increasing the risk of depression and dementia. In neurons, mitochondria at synapses are vital for maintenance of synaptic function and transmission through normal mitochondrial dynamics, proper distribution and trafficking, energy metabolism, and synaptic calcium modulation. Imbalance of mitochondria dynamics contributes to oxidative stress- and hyperglycemia-induced alterations in mitochondrial morphology and function. The underlying molecular and cellular mechanisms are poorly understood. RAGE (Receptor for Advanced Glycation Endproducts, AGEs) is a multiligand receptor of the immunoglobulin superfamily. RAGE functions as a signal transducing cell surface acceptor site for AGEs, S100/calgranuline, or amyloid-beta peptide (A). Interaction of RAGE and its ligands increases oxidative stress, inflammation, A accumulation, and impairs synaptic function and learning memory. However, the impact of RAGE on mitochondrial and synaptic function in diabetes mellitus (DM) remains unknown. It is unclear whether RAGE is important mediator for AGE- and diabetes-induced mitochondrial and synaptic stress; whether and how RAGE-dependent signal transduction contributes to alterations in mitochondrial and synaptic structure and function in DM. In our preliminary studies, we have revealed a number of novel findings related to the regulation of mitochondria by RAGE. First, genetic depletion of neuronal RAGE alleviates AGE-induced synaptic dysfunction. Blockade of RAGE signaling rescued high glucose-induced mitochondrial alterations. Second, genetic depletion of global RAGE rescued abnormal mitochondrial morphology/function and synaptic injury in diabetes mouse brains as well as induction of proinflammatory mediators. Finally, RAGE exhibited biochemical interaction with DLP1 (dynamin-like protein 1), suggesting that DLP1 serves as a novel substrate to mediate the effect of RAGE on mitochondrial distribution. Further, inhibition of excessive mitochondrial fission or RAGE attenuated DM-induced induction of proinflammatory cytokines and chemokine. These findings lead us to hypothesize that in diabetes, chronic and sustained accumulation of AGEs and proinflammatory RAGE ligands, and upregulation of RAGE, perturbs mitochondrial structure and function, and oxidative stress, leading to synaptic mitochondrial dysfunction and synaptic injury in DM. This proposal will address the fundamental questions of whether RAGE is a key player in diabetes-induced mitochondrial and synaptic injury and whether blockade of RAGE restores mitochondrial and neuronal function.

Public Health Relevance

The goal of this proposal is to gain new insight into the role of RAGE in diabetes-induced mitochondrial and synaptic injury and possible cross talk of molecular and cellular mechanisms between diabetes and Alzheimer's disease. Our findings will provide further substantial support for targeting RAGE as a key therapeutic strategy in diabetes in particular for prevention and treatment of mitochondrial and synaptic degeneration at the early stage of disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS089116-04
Application #
9487027
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Corriveau, Roderick A
Project Start
2015-08-01
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Yan, Shi Fang; Akhter, Firoz; Sosunov, Alexander A et al. (2018) Identification and Characterization of Amyloid-? Accumulation in Synaptic Mitochondria. Methods Mol Biol 1779:415-433
Fang, Fang; Yu, Qing; Arancio, Ottavio et al. (2018) RAGE mediates A? accumulation in a mouse model of Alzheimer's disease via modulation of ?- and ?-secretase activity. Hum Mol Genet 27:1002-1014
Kalani, Komal; Yan, Shi Fang; Yan, Shirley ShiDu (2018) Mitochondrial permeability transition pore: a potential drug target for neurodegeneration. Drug Discov Today 23:1983-1989
Du, Fang; Yu, Qing; Chen, Allen et al. (2018) Astrocytes Attenuate Mitochondrial Dysfunctions in Human Dopaminergic Neurons Derived from iPSC. Stem Cell Reports 10:366-374
Akhter, F; Chen, D; Yan, S F et al. (2017) Mitochondrial Perturbation in Alzheimer's Disease and Diabetes. Prog Mol Biol Transl Sci 146:341-361
Yu, Qing; Du, Fang; Douglas, Justin T et al. (2017) Mitochondrial Dysfunction Triggers Synaptic Deficits via Activation of p38 MAP Kinase Signaling in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells. J Alzheimers Dis 59:223-239
Du, Fang; Yu, Qing; Yan, Shijun et al. (2017) PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease. Brain 140:3233-3251
Criscuolo, Chiara; Fontebasso, Veronica; Middei, Silvia et al. (2017) Entorhinal Cortex dysfunction can be rescued by inhibition of microglial RAGE in an Alzheimer's disease mouse model. Sci Rep 7:42370
Fang, Du; Qing, Yu; Yan, Shijun et al. (2016) Development and Dynamic Regulation of Mitochondrial Network in Human Midbrain Dopaminergic Neurons Differentiated from iPSCs. Stem Cell Reports 7:678-692
Fang, Du; Yan, Shijun; Yu, Qing et al. (2016) Mfn2 is Required for Mitochondrial Development and Synapse Formation in Human Induced Pluripotent Stem Cells/hiPSC Derived Cortical Neurons. Sci Rep 6:31462

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