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. 2011 Dec 6;108(49):E1339-48. doi: 10.1073/pnas.1102349108. Epub 2011 Oct 31.


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 β-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-β peptide (Aβ) 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 Aβ oligomer-sensitive manner. Further, FGF2 enhances Aβ phagocytosis in primary cultured microglia, and reduces Aβ 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / therapy
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Cells, Cultured
  • Cognition Disorders / genetics
  • Cognition Disorders / metabolism*
  • Cognition Disorders / therapy
  • Dentate Gyrus / metabolism
  • Dentate Gyrus / pathology
  • Dependovirus / genetics
  • Disease Models, Animal
  • Fibroblast Growth Factor 2 / genetics
  • Fibroblast Growth Factor 2 / metabolism*
  • Genetic Therapy / methods
  • Genetic Vectors / genetics
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Humans
  • Immunohistochemistry
  • Long-Term Potentiation / physiology
  • Maze Learning / physiology
  • Mice
  • Mice, 129 Strain
  • Mice, Transgenic
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / therapy
  • Neurogenesis / physiology
  • Neurons / metabolism
  • Neurons / pathology
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Presenilin-1
  • Proto-Oncogene Proteins c-fos
  • Fibroblast Growth Factor 2