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.

Standardized Herbal Formula PM012 Decreases Cognitive Impairment and Promotes Neurogenesis in the 3xTg AD Mouse Model of Alzheimer’s Disease

“…Indeed, the hippocampus is affected early in AD and memory impairment related to hippocampal damage is associated with the deregulation of neurogenesis [52]. The subventricular zone of the lateral ventricle and the subgranular layer of the dentate gyrus in the hippocampus are both associated with adult neurogenesis [16][17][18][19]. It has been proven that a dramatic decline in neurogenesis contributes to the impairment of learning and memory in AD models [20,53].…”

“…Many studies have provided strong evidence that the loss of hippocampal neurogenesis contributes to the development of AD and the impairment of learning and memory [16][17][18][19]. Several studies using a transgenic mouse model of AD have shown significant alterations in the process of adult neurogenesis in the hippocampus [20].…”

Formoterol, a Long-Acting β2 Adrenergic Agonist, Improves Cognitive Function and Promotes Dendritic Complexity in a Mouse Model of Down Syndrome

“…Basic fibroblast growth factor (FGF2) plays a key role in proliferation and differentiation of neuronal progenitors (36). We found approximately 70% reduction in Fgf2 messenger RNA (mRNA) levels in the DG of Ts65Dn mice, compared with 2N counterparts.…”

Inhibition of Endoplasmic Reticulum Stress is Involved in the Neuroprotective Effect of bFGF in the 6-OHDA-Induced Parkinson’s Disease Model

“…bFGF has generated considerable excitement as a promising therapy for neurodegenerative diseases, including PD [11], Huntington's disease [40] and Alzheimer's disease [41]. bFGF appeared to be efficacious in two Phase II clinical trials for stroke, but failed in the large scale Phase III trial [42,43].…”

“…Primary hippocampal neurons were seeded into 96-well plates and treated with 6-OHDA (50, 100, 150, 200 and 400 μM) for 24 h with or without bFGF (10,20,40 and 80 ng/mL). After 24 h incubation, cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.…”