TY - JOUR
T1 - Central insulin resistance and synaptic dysfunction in intracerebroventricular-streptozotocin injected rodents
AU - Shonesy, Brian C.
AU - Thiruchelvam, Kariharan
AU - Parameshwaran, Kodeeswaran
AU - Rahman, Engy Abdel
AU - Karuppagounder, Senthilkumar S.
AU - Huggins, Kevin W.
AU - Pinkert, Carl A.
AU - Amin, Rajesh
AU - Dhanasekaran, Muralikrishnan
AU - Suppiramaniam, Vishnu
PY - 2012/2
Y1 - 2012/2
N2 - 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.
AB - 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.
KW - AMPAR
KW - Alzheimer's disease
KW - Hippocampus
KW - Ic-STZ
KW - Insulin resistance
KW - Long-term potentiation (LTP)
KW - NMDAR
KW - Synaptic plasticity
UR - http://www.scopus.com/inward/record.url?scp=82755187412&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=82755187412&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2010.12.002
DO - 10.1016/j.neurobiolaging.2010.12.002
M3 - Article
C2 - 21256630
AN - SCOPUS:82755187412
VL - 33
SP - 430.e5-430.e18
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 2
ER -