Effects Of Intranasal Administration Of Liposome Tat-haFGF_14-154 On Alzheimer's Disease In APP/PS1 Mice And Its Mechanism

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-haFGF_14-154 is markedly increased when loaded cationic liposomes for intranasal delivery intranasally administered to APP/PS1 mice.Our results demonstrated that liposomal Tat-haFGF_14-154 treatment significantly ameliorated behavioral deficits,relieved brain A? burden,and increased the expression and activity of a disintegrin and metalloproteinase domain-containing protein10?ADAM10?in the brain.Tat-haFGF_14-154 antagonized A?1-42-induced cell death and structural damage in rat primary neurons in an ADAM10-dependent manner,which,in turn,was by 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-haFGF_14-154 rescue.Thus,Tat-haFGF_14-154 activates the IRE1?/XBP1 pathway of the unfolded protein response?UPR?against the ER stress induced by A?,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-IRE1?/XBP1 pathway as a key factor in the mechanism of neuroprotection for Tat-haFGF_14-154.