Central insulin resistance and synaptic dysfunction in intracerebroventricular-streptozotocin injected rodents.
To better understand the role of insulin signaling in the development of Alzheimer's disease (AD), we utilized an animal model (intracerebroventricular injection of streptozotocin-ic-streptozotocin (STZ)) that displays insulin resistance only in the brain and exhibits AD pathology. In this model, deficits in hippocampal synaptic transmission and long-term potentiation (LTP) were observed. The decline in LTP correlated with decreased expression of NMDAR subunits NR2A and NR2B. The deficits in LTP were accompanied by changes in the expression and function of synaptic AMPARs. In ic-STZ animals, an alteration in integrin-linked kinase (ILK)-glycogen synthase kinase 3 beta (GSK-3-β) signaling was identified (p < 0.05). Similarly, there was decreased expression (p < 0.05) of brain derived neurotropic factor (BDNF) and stargazin, an AMPAR auxiliary subunit; both are required for driving AMPA receptors to the surface of the postsynaptic membrane. Our data illustrate that altered ILK-GSK-3β signaling due to impaired insulin signaling may decrease the trafficking and function of postsynaptic glutamate receptors; thereby, leading to synaptic deficits contributing to memory loss.
Department of Pharmacal Sciences, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
Brian C
BC
Shonesy
Kariharan
K
Thiruchelvam
Kodeeswaran
K
Parameshwaran
Engy Abdel
EA
Rahman
Senthilkumar S
SS
Karuppagounder
Kevin W
KW
Huggins
Carl A
CA
Pinkert
Rajesh
R
Amin
Muralikrishnan
M
Dhanasekaran
Vishnu
V
Suppiramaniam
D000544:Alzheimer Disease / Q000139:chemically induced / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D007276:Injections, Intraventricular; D007333:Insulin Resistance; D017774:Long-Term Potentiation; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism*; D013311:Streptozocin / Q000008:administration & dosage*; D013569:Synapses; D009435:Synaptic Transmission
D017470:Receptors, Glutamate; D013311:Streptozocin