The novel squamosamide derivative FLZ enhances BDNF/TrkB/CREB signaling and inhibits neuronal apoptosis in APP/PS1 mice.
OBJECTIVE
The aim of this study was to study the effects of compound FLZ, a novel cyclic derivative of squamosamide from Annona glabra, on brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/cAMP response element-binding protein (CREB) signaling and neuronal apoptosis in the hippocampus of the amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mice.


METHODS
APP/PS1 mice at the age of 5 months and age-matched wild-type mice (WT) were intragastrically administered FLZ (150 mg/kg) or vehicle [0.05% carboxymethyl cellulose sodium (CMC-Na)] daily for 20 weeks. The levels of BDNF in the hippocampus of WT and APP/PS1 mice were then measured by immunohistochemistry and Western blot analysis. Neuronal apoptosis in mouse hippocampus was detected by Nissl staining. Expression of NGF, NT3, pTrkB (Tyr515)/TrkB, pAkt (Ser473)/Akt, pERK/ERK, pCREB (Ser133)/CREB, Bcl-2/Bax, and active caspase-3 fragment/caspase-3 in the hippocampus of WT and APP/PS1 mice was detected by Western blot analysis.


RESULTS
Compared with vehicle-treated APP/PS1 mice, FLZ (150 mg/kg) significantly increased BDNF and NT3 expression in the hippocampus of APP/PS1 mice. In addition, FLZ promoted BDNF high-affinity receptor TrkB phosphorylation and activated its downstream ERK, thus increasing phosphorylation of CREB at Ser133 in the hippocampus of APP/PS1 mice. Moreover, FLZ showed neuroprotective effects on neuronal apoptosis by increasing the Bcl-2/Bax ratio and decreasing the active caspase-3 fragment/caspase-3 ratio in the hippocampus of APP/PS1 mice.


CONCLUSIONS
FLZ exerted neuroprotection at least partly through enhancing the BDNF/TrkB/CREB pathway and inhibiting neuronal apoptosis in APP/PS1 mice, which suggests that FLZ can be explored as a potential therapeutic agent in long-term Alzheimer's disease therapy.
Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Ning
N
Li
Geng-tao
GT
Liu
D000544:Alzheimer Disease / Q000188:drug therapy*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D044482:Benzeneacetamides / Q000494:pharmacology* / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010636:Phenols / Q000494:pharmacology* / Q000627:therapeutic use; D053764:Presenilin-1 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D044482:Benzeneacetamides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D010636:Phenols; D053764:Presenilin-1; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C084439:squamosamide; D020813:Receptor, trkB; D053148:Caspase 3