title: FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer's disease and has therapeutic implications for neurocognitive disorders.
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 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.
authors: Department of Pharmacology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors: Tomomi
authors: T
authors: Kiyota
authors: Kaitlin L
authors: KL
authors: Ingraham
authors: Michael T
authors: MT
authors: Jacobsen
authors: Huangui
authors: H
authors: Xiong
authors: Tsuneya
authors: T
authors: Ikezu
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D018891:Dentate Gyrus / Q000378:metabolism / Q000473:pathology; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D017774:Long-Term Potentiation / Q000502:physiology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D016760:Proto-Oncogene Proteins c-fos; D016222:Fibroblast Growth Factor 2