IFN‐γ enhances neurogenesis in wild‐type mice and in a mouse model of Alzheimer's disease

Abstract

The generation of new neurons and glia from a precursor stem cell appears to take place in the adult brain. However, new neurons generated in the dentate gyrus decline sharply with age and to an even greater extent in neurodegenerative diseases. Here we raise the question whether peripheral immune mechanisms can generate immunity to such deficits in neuronal repair. We demonstrate that in contrast to primarily innate immunity cytokines, such as interleukin-6 and tumor necrosis factor-alpha, the adaptive immunity cytokine IFN-gamma enhances neurogenesis in the dentate gyrus of adult mice and improves the spatial learning and memory performance of the animals. In older mice, the effect of IFN-gamma is more pronounced in both wild-type mice and mice with Alzheimer's-like disease and is associated with neuroprotection. In addition, IFN-gamma reverses the increase in oligodendrogenesis observed in a mouse model of Alzheimer's disease. We demonstrate that limited amounts of IFN-gamma in the brain shape the neuropoietic milieu to enhance neurogenesis, possibly representing the normal function of the immune system in controlling brain inflammation and repair.

Interferon-γ Differentially Affects Alzheimer’s Disease Pathologies and Induces Neurogenesis in Triple Transgenic-AD Mice

“…[42][43][44] Although untested, there is a possibility that IFN␥ antagonizes these latter pathways or acts via a completely unrelated mechanism to suppress tau hyperphosphorylation. Signs of marked neurogenesis were also evident in IFN␥-expressing 3ϫTg-AD mice, a finding confirmed in a different murine AD model in the recent report from Baron et al 36 IFN␥ has been shown to promote neuronal differentiation in vitro, 45,46 neuronal plasticity, and receptor clustering. 47 Moreover, human neural stem/progenitor cell cultures express the cognate receptors for IFN␥, termed IFN-␥-R␣ and IFN-␥-R␤, and are driven toward a neuronal fate when cultured in the presence of IFN␥.…”

“…Perhaps more pertinent to our present study, Baron et al 36 used a similar transgenic approach for which they recently reported that mice arising from a cross between a transgenic line expressing IFN␥ from an oligodendrocyte-specific promoter and an human APP-overexpressing mouse model of AD resulted in marked enhancement of neurogenesis within the dentate gyrus and improved spatial learning and memory. Moreover, these compound transgenic mice showed evidence of modest inflammatory marker transcript increases, neuroprotection as measured by enhanced synaptophysin staining densities within the highly innervated CA1 and CA3 regions of the hippocampus, and suppression of oligodendrogenesis.…”

NK Cells in Central Nervous System Disorders

“…As a comparable example, liver NK cells were implicated in the emergence of fulminant hepatic failure following mouse hepatitis virus infection, whereas the depletion of NK cells limited liver damage and increased animal survival (90). Alternatively, IFN-g was also associated with both neuronal protection and repair by modulation of microglia properties (91), so we can propose that NK cells secreting IFN-g following infection may have a neuroprotective function (Fig. 4).…”

Th1 Polarization of T Cells Injected into the Cerebrospinal Fluid Induces Brain Immunosurveillance

“…However, although it is believed to underlie the pathogenesis of MS (13)(14)(15)(16), in other neurodegenerative processes including brain injury (17,18), amyotrophic lateral sclerosis (19), stroke (20), and Alzheimer's disease (AD), T cell infiltration into the CNS has been implicated either as exacerbating neurodegeneration (21)(22)(23) or, in other instances, as beneficial. Regulatory cytokine profiles of certain T cell subsets (24)(25)(26) or the ability of T cells to secrete neurotrophic factors (27,28) have been suggested as mechanisms underlying the beneficial effects of T cell infiltration into the CNS. However, a key stage of this process, namely the mechanisms responsible for the infiltration of CSF-derived T cells into the CNS parenchyma, is yet unidentified.…”