From determining brain insulin resistance in a sporadic Alzheimer’s disease model to exploring the region-dependent effect of intranasal insulin

Published: 14 June 2022| Version 2 | DOI: 10.17632/k2rs33vsyz.2
Ana Knezovic, Stjepan Budisa, Ana Babić Perhoč, Jan Homolak, Jelena Osmanovic Barilar


Impaired response to insulin has been linked to many neurodegenerative disorders like Alzheimer’s disease (AD). Animal model of sporadic AD has been developed by intracerebroventricular (icv) administration of streptozotocin (STZ), which given peripherally causes insulin resistance. Difficulty in demonstrating insulin resistance in this model led to our aim: to determine brain regional and peripheral response after intranasal (IN) administration of insulin in control and STZ-icv rats, by exploring peripheral and central metabolic parameters. One month after STZ-icv or vehicle-icv administration to 3-months-old male Wistar rats, cognitive status was determined after which rats received 2 IU of fast-acting insulin aspart intranasally (CTR+INS; STZ+INS) or saline only (CTR and STZ). Rats were sacrificed two hours after administration and metabolic and glutamatergic parameters were measured in plasma, CSF and the brain. Insulin and STZ increased amyloid-β concentration in plasma (CTR+INS and STZ vs CTR), while there was no effect on glucose and insulin plasma and CSF levels. INS normalized the levels of c-fos in temporal cortex of STZ+INS vs STZ (co-localized with neurons), while hypothalamic c-fos was found co-localized with the microglial marker. STZ and insulin brain region-specifically altered the levels and activity of proteins involved in cell metabolism and glutamate signaling. Central changes found after INS in STZ-icv rats suggest hippocampal and cortical insulin sensitivity. Altered hypothalamic metabolic parameters of STZ-icv rats were not normalized by INS, indicating possible hypothalamic insulin insensitivity. Brain insulin sensitivity depends on the affected brain region and presence of metabolic dysfunction induced by STZ-icv administration.



Neuropharmacology, Alzheimer's Disease