Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1α, and phosphorylates GSK3β in P301L tau transgenic mice

Abstract

Deferoxamine (DFO), a metal chelator, has been previously reported to slow the loss of spatial memory in a mouse model of amyloid accumulation when delivered intranasally (IN). In this study, we determined whether IN DFO also has beneficial effects in the P301L mouse, which accumulates hyperphosphorylated tau. Mice were intranasally treated three times per week with either 10% DFO (2.4 mg) or saline for 5 months, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with Western blot and ELISA. Wild-type (WT) mice statistically outperformed transgenic (TG) saline mice in the radial arm water maze, while performance of TG-DFO mice was not different than WT mice, suggesting improved performance in the radial arm water maze. Other behavioral changes were not evident. Beneficial changes in brain biochemistry were evident in DFO-treated mice for several proteins. The TG mice had significantly less pGSK3β and HIF-1α, with more interleukin-1β and total protein oxidation than wild-type controls, and for each protein, DFO treatment significantly reduced these differences. There was not a significant decrease in phosphorylated tau in brain tissue of DFO-treated mice at the sites we measured. These data suggest that IN DFO is a potential treatment not only for Alzheimer's disease, but also for other neurodegenerative diseases and psychiatric disorders in which GSK3β and HIF-1α play a prominent role.

Intranasal deferoxamine engages multiple pathways to decrease memory loss in the APP/PS1 model of amyloid accumulation

“…Specifically, IN DFO increased phosphorylation of GSK at Ser9, decreasing GSK activity and increasing ˇ-catenin. This increase in pGSK3ˇ and ˇ-catenin was seen in a tau mouse model in Fine et al [7], though the increase in ˇ-catenin in that study was not significant. This may be related to the 10x dose difference (2.4 mg DFO vs 0.24 mg DFO), or to the time difference between last dose and euthanasia, which was 30 min in Fine et al [7], and 24 h in the current study.…”

“…The changes in soluble amyloid as well as oxidation suggest that DFO may be affecting the amyloid cascade. DFO has also been shown to be beneficial in the P301L tau model of AD, and protective effects were measured via pGSK, inflammation and oxidation, though no changes in tau were measured [7]. Because IN DFO is beneficial in several models of AD, and in other neurodegenerative diseases, it suggests DFO engages multiple targets to elicit a pleiotropic protective response in the brain.…”

“…To assess working memory, radial arm water maze (RAWM) was performed as in Fine et al [7], except there were 4 trials/day, tests proceeded for 9 days, and a penalty was assessed for noncompliance. Specifically, if a mouse had three or less errors and 60 s escape latency, it was assessed a penalty of eight errors.…”

“…The 9 days of data were divided into three blocks of 3 days. For reference memory, Morris water maze (MWM) was performed as in Fine et al [7], except that hidden platform tests consisted of 5 successive days at one block of 4 trials/day. The elevated plus maze, open field, and rotarod were all performed exactly as in Fine et al [7].…”

“…Intranasal (IN) delivery is a non-invasive method of targeting drugs directly from the nose to the brain, and allows for DFO to be delivered with minimal systemic exposure. Intranasal delivery of DFO has been shown to have benefit in several animal models of Alzheimer's and Parkinson's disease [7][8][9][10]. Hanson et al [8] showed a behavioral benefit of IN DFO in an amyloid mouse model, though it did not address any biochemical mechanisms, and behavioral analysis was limited to a single memory task.…”