Peripheral Neutralization of Nerve Growth Factor Induces Immunosympathectomy and Central Neurodegeneration in Transgenic Mice

We previously showed that anti-nerve growth factor (NGF) antibodies expressed in transgenic mice (AD11) elicit a progressive neurodegeneration, comprising the triad of Alzheimer's disease (AD) hallmarks: cholinergic loss, tau hyperphosphorylation, and amyloid-beta peptide formation. However, since anti-NGF antibodies are produced both in the brain and in peripheral tissues of AD11 mice, the contribution of peripheral neutralization of NGF to the onset of brain neurodegeneration was still unexplored. To address this question, we characterized a line of transgenic mice (AD10) in which anti-NGF antibodies are obligatorily produced only in lymphocytes, being initially found in blood. In AD10 mice, peripheral NGF neutralization elicits shrinkage of superior cervical ganglia (immunosympathectomy) and, as a consequence of this, peripheral anti-NGF antibodies cross the blood brain barrier (BBB) and reach the brain, generating an NGF-dependent neurodegeneration, largely superimposable to that observed in AD11 mice. This demonstrates that peripherally originated anti-NGF antibodies can generate a neurodegeneration in the central nervous system of an animal model. Consistently, peripherally-delivered NGF is effective in preventing the onset of the central cholinergic deficit. These findings could have a direct relevance for some human sporadic AD cases, highlighting the role of the BBB disruption and suggesting a causally relevant role of circulating antibodies in AD pathology.