Abstract:
:Acid fibroblast growth factor (aFGF) has shown neuroprotection in Alzheimer's disease (AD) models in previous studies, yet its mechanism is still uncertain. Here we report that the efficacy of Tat-haFGF14-154 is markedly increased when loaded cationic liposomes for intranasal delivery are intranasally administered to APP/PS1 mice. Our results demonstrated that liposomal Tat-haFGF14-154 treatment significantly ameliorated behavioral deficits, relieved brain Aβ burden, and increased the expression and activity of disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in the brain. Tat-haFGF14-154 antagonized Aβ1-42-induced cell death and structural damage in rat primary neurons in an ADAM10-dependent manner, which, in turn, was promoted by the activation of XBP1 splicing and modulated by the PI3K-CREB pathway. Both knockdown of ADAM10 and inhibition of PI3K (LY294002) negated Tat-haFGF14-154 rescue. Thus, Tat-haFGF14-154 activates the IRE1α/XBP1 pathway of the unfolded protein response (UPR) against the endoplasmic reticulum (ER) stress induced by Aβ, and, subsequently, the nuclear translocation of spliced XBP1 (XBP1s) promotes transcription of ADAM10. These results highlight the important role of ADAM10 and its activation through the PI3K-CREB-IRE1α/XBP1 pathway as a key factor in the mechanism of neuroprotection for Tat-haFGF14-154.
journal_name
Mol Ther Nucleic Acidsjournal_title
Molecular therapy. Nucleic acidsauthors
Meng T,Cao Q,Lei P,Bush AI,Xiang Q,Su Z,He X,Rogers JT,Chiu IM,Zhang Q,Huang Ydoi
10.1016/j.omtn.2017.05.004subject
Has Abstractpub_date
2017-06-16 00:00:00pages
439-452issn
2162-2531pii
S2162-2531(17)30174-9journal_volume
7pub_type
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