TY - JOUR
T1 - Combination of Insulin with a GLP1 Agonist Is Associated with Better Memory and Normal Expression of Insulin Receptor Pathway Genes in a Mouse Model of Alzheimer’s Disease
AU - Robinson, Ari
AU - Lubitz, Irit
AU - Atrakchi-Baranes, Dana
AU - Licht-Murava, Avital
AU - Katsel, Pavel
AU - Leroith, Derek
AU - Liraz-Zaltsman, Sigal
AU - Haroutunian, Vahram
AU - Beeri, Michal Schnaider
N1 - Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/4/15
Y1 - 2019/4/15
N2 - Disruption of brain insulin signaling may explain the higher Alzheimer’s disease (AD) risk among type 2 diabetic (T2D) patients. There is evidence from in vitro and human postmortem studies that combination of insulin with hypoglycemic medications is neuroprotective and associated with less amyloid aggregation. We examined the effect of 8-month intranasal administration of insulin, exenatide (a GLP-1 agonist), combination therapy (insulin + exenatide) or saline, in wild-type (WT) and an AD-like mouse model (Tg2576). Mice were assessed for learning, gene expression of key mediators and effectors of the insulin receptor signaling pathway (IRSP-IRS1, AKT1, CTNNB1, INSR, IRS2, GSK3B, IGF1R, AKT3), and brain Amyloid Beta (Aβ) levels. In Tg2576 mice, combination therapy reduced expression of IRSP genes which was accompanied by better learning. Cortical Aβ levels were decreased by 15–30% in all groups compared to saline but this difference did not reach statistical significance. WT mice groups, with or without treatment, did not differ in any comparison. Disentangling the mechanisms underlying the potential beneficial effects of combination therapy on the IR pathway and AD-like behavior is warranted.
AB - Disruption of brain insulin signaling may explain the higher Alzheimer’s disease (AD) risk among type 2 diabetic (T2D) patients. There is evidence from in vitro and human postmortem studies that combination of insulin with hypoglycemic medications is neuroprotective and associated with less amyloid aggregation. We examined the effect of 8-month intranasal administration of insulin, exenatide (a GLP-1 agonist), combination therapy (insulin + exenatide) or saline, in wild-type (WT) and an AD-like mouse model (Tg2576). Mice were assessed for learning, gene expression of key mediators and effectors of the insulin receptor signaling pathway (IRSP-IRS1, AKT1, CTNNB1, INSR, IRS2, GSK3B, IGF1R, AKT3), and brain Amyloid Beta (Aβ) levels. In Tg2576 mice, combination therapy reduced expression of IRSP genes which was accompanied by better learning. Cortical Aβ levels were decreased by 15–30% in all groups compared to saline but this difference did not reach statistical significance. WT mice groups, with or without treatment, did not differ in any comparison. Disentangling the mechanisms underlying the potential beneficial effects of combination therapy on the IR pathway and AD-like behavior is warranted.
KW - Alzheimer’s disease
KW - Exenatide
KW - Insulin
KW - T2D
UR - http://www.scopus.com/inward/record.url?scp=85059891997&partnerID=8YFLogxK
U2 - 10.1007/s12031-019-1257-9
DO - 10.1007/s12031-019-1257-9
M3 - Article
C2 - 30635783
AN - SCOPUS:85059891997
SN - 0895-8696
VL - 67
SP - 504
EP - 510
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 4
ER -