Human Basic Fibroblast Growth Factor Inhibits Tau Phosphorylation via the PI3K/Akt-GSK3β Signaling Pathway in a 6-Hydroxydopamine-Induced Model of Parkinson's Disease

Abstract

Background: Basic fibroblast growth factor (bFGF) has been increasingly investigated due to its neuroprotection in neurodegenerative disorders. Because there are still no cures for any of these disorders, it is crucial to identify new therapeutic targets and screen potential drugs. The increased phosphorylation of tau at Ser³⁹⁶ leads to intracellular tau accumulation, which forms neurofibrillary tangles in Parkinson's disease (PD). In this study, neuroprotection by bFGF was observed, and the mechanisms related to its regulation of phosphorylated tau were investigated. Methods: bFGF-loaded liposome carriers were intranasally administered to rats. The neuroprotective effects of bFGF were assessed in a PD model induced by 6-hydroxydopamine (6-OHDA) in vivo and in vitro. The phosphorylation of tau was measured, and the PI3K/Akt-GSK3β signaling pathway was investigated. Results: Our study demonstrated that liposomes markedly assisted in the delivery of bFGF to the striatum and substantia nigra of rats and enhanced the neuroprotective effects of bFGF on dopaminergic neurons. bFGF treatment significantly ameliorated the behavioral deficits induced by 6-OHDA, rescued the loss of tyrosine hydroxylase-positive neurons and increased the number of Nissl bodies. bFGF reduced the phosphorylation of tau and GSK3β and increased the phosphorylation of PI3K/Akt. Conclusion: Liposomes markedly assisted in the delivery of bFGF to the brain and enhanced the neuroprotective effects of bFGF by inhibiting the phosphorylation of tau. bFGF down-regulated the phosphorylation of tau by increasing the phosphorylation of GSK3β via the PI3K/Akt signaling pathway. These findings provide a new vision of bFGF as a potential therapy for PD.

Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid

“…PG itself, administered intranasally, has been used as a therapy by the Voelker group to effectively inhibit respiratory syncytial virus infection (Numata et al, 2010; Numata et al, 2013) and influenza A virus (Numata et al, 2012). Moreover, lipid based colloidal carriers are able to cross the blood brain barrier (BBB) when administered intranasally (Ganesan et al, 2018; Mittal et al, 2014; Patel and Patel, 2017; Tapeinos et al, 2017) and have recently been shown to be efficient drug delivery vehicles in the treatment of intrinsic brain tumors (van Woensel et al, 2013) and neurodegenerative diseases including Alzheimer’s (Agrawal et al, 2018; Tapeinos et al, 2017) and Parkinson’s (Tapeinos et al, 2017; Yang et al, 2016). Given the historical difficulties in treating the neurological effects of NPC disease, the development of a minimally invasive, effective treatment with intrinsic ability to cross the BBB is of interest.…”

Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences

“…In the normal adult brain, CDK5 activated by protein p35 (or p39) phosphorylates Ser199 and Ser202, and GSK3β is able to phosphorylate only Ser202. If GSK3β is up-regulated, it recognizes the 202pSPGT205 site created e.g., by p35/CDK5, and efficiently phosphorylates Thr205 [105,106]. Additional phosphorylation at Ser208 was achieved in vitro by addition of the rat brain extract [103].…”

Tat-haFGF 14–154 Upregulates ADAM10 to Attenuate the Alzheimer Phenotype of APP/PS1 Mice through the PI3K-CREB-IRE1α/XBP1 Pathway

“…Our previous studies showed that intranasal administration of TAT-haFGF could improve cognition and reduce Aβ deposits more significantly in APP/PS1 mice compared with intravenous injection 18, 21, 22, 23. In an animal model of Parkinson’s disease induced by 6-OHDA, liposomes markedly assisted the delivery of basic fibroblast growth factor (bFGF) to the striatum and substantia nigra (SN), and they enhanced the neuroprotective effects of bFGF on dopaminergic neurons 46 . Liposomes also enhanced the levels of aFGF significantly in the EC, accompanied by amelioration in cognitive and non-cognitive behavioral deficits.…”