Enhanced Hippocampal Neurogenesis in APP/Ps1 Mouse Model of Alzheimer's Disease After Implantation of VEGF-loaded PLGA Nanospheres.
During adult life, hippocampus is an important brain region involved in neurogenesis. The generation and cell death of newly generated neuronal cells in this region have critical roles in brain maintenance and alterations in these processes are seen in Alzheimer's disease (AD). For the purpose of carrying out a neuroregenerative strategy, we propose a novel approach based on the encapsulation of vascular endothelial growth factor (VEGF) in poly (lactic co-glycolic acid) (PLGA) biodegradable nanospheres (NS) administered by craniotomy to stimulate the proliferation of neuronal precursors in a transgenic mouse model of AD. VEGF loaded nanospheres were prepared by double emulsion solvent evaporation technique, obtaining 200 nm nanospheres with a biphasic release profile. After demonstrating their efficacy in the proliferation and differentiation of neuronal cell cultures, in vivo studies were carried out. 3 months after VEGF-NS were implanted directly into the cerebral cortex of APP/Ps1 mice, the determination of BrdU(+) cells in the whole hippocampal region and specifically in the dentate gyrus, demonstrated a significantly enhanced cellular proliferation in VEGF-NS treated group. These results were also confirmed showing an increased number of DCX(+) and NeuN(+) cells. Hence, PLGA-VEGF nanospheres may be a potential strategy to modulate proliferative neuronal progenitors in the hippocampal region, and therefore, provide new insight for future therapeutic approaches in AD.
E
E
Herran
R
R
Perez-Gonzalez
M
M
Igartua
J L
JL
Pedraz
E
E
Carro
Neuroscience Laboratory, Research Center, Hospital Universitario 12 de Octubre, Spain. rosa.hernandez@ehu.es.
R M
RM
Hernandez
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D063566:Biodegradable Plastics / Q000737:chemistry; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D004337:Drug Carriers / Q000737:chemistry; D004343:Drug Implants / Q000737:chemistry; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008822:Mice, Transgenic; D054118:Nanospheres / Q000737:chemistry; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*
C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D063566:Biodegradable Plastics; C000714847:Dcx protein, mouse; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D004337:Drug Carriers; D004343:Drug Implants; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D042461:Vascular Endothelial Growth Factor A; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid