FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders.
Proc Natl Acad Sci U S A
; 108(49): E1339-48, 2011 Dec 06.
Article
em En
| MEDLINE
| ID: mdl-22042871
ABSTRACT
The adult hippocampus plays a central role in memory formation, synaptic plasticity, and neurogenesis. The subgranular zone of the dentate gyrus contains neural progenitor cells with self-renewal and multilineage potency. Transgene expression of familial Alzheimer's disease-linked mutants of ß-amyloid precursor protein (APP) and presenilin-1 leads to a significant inhibition of neurogenesis, which is potentially linked to age-dependent memory loss. To investigate the effect of neurogenesis on cognitive function in a relevant disease model, FGF2 gene is delivered bilaterally to the hippocampi of APP+presenilin-1 bigenic mice via an adenoassociated virus serotype 2/1 hybrid (AAV2/1-FGF2). Animals injected with AAV2/1-FGF2 at a pre- or postsymptomatic stage show significantly improved spatial learning in the radial arm water maze test. A neuropathological investigation demonstrates that AAV2/1-FGF2 injection enhances the number of doublecortin, BrdU/NeuN, and c-fos-positive cells in the dentate gyrus, and the clearance of fibrillar amyloid-ß peptide (Aß) in the hippocampus. AAV2/1-FGF2 injection also enhances long-term potentiation in another APP mouse model (J20) compared with control AAV2/1-GFP-injected littermates. An in vitro study confirmed the enhanced neurogenesis of mouse neural stem cells by direct AAV2/1-FGF2 infection in an Aß oligomer-sensitive manner. Further, FGF2 enhances Aß phagocytosis in primary cultured microglia, and reduces Aß production from primary cultured neurons after AAV2/1-FGF2 infection. Thus, our data indicate that virus-mediated FGF2 gene delivery has potential as an alternative therapy of Alzheimer's disease and possibly other neurocognitive disorders.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator 2 de Crescimento de Fibroblastos
/
Transtornos Cognitivos
/
Doenças Neurodegenerativas
/
Doença de Alzheimer
/
Hipocampo
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2011
Tipo de documento:
Article