Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice

doi:10.1073/pnas.0500195102

Intranasal administration of nerve growth factor (NGF) rescues recognition memory deficits in AD11 anti-NGF transgenic mice

^*Lay Line Genomics S.p.A., Via di Castel Romano 100, 00128 Rome, Italy; ^†Institute of Neuroscience, Consiglio Nazionale delle Ricerche, Via Moruzzi 1, 56100 Pisa, Italy; ^‡Scuola Normale Superiore, Piazza dei Cavalieri 7, I-56100 Pisa, Italy; ^§Department of Psychology, Florence University, Via San Niccolò 93, 4-50121 Florence, Italy; ^¶International School for Advanced Studies, Via Beirut 2-4, 34014 Trieste, Italy; and ^∥European Brain Research Institute, Via Fosso di Fiorano 65, 00143 Rome, Italy

Communicated by Rita Levi-Montalcini, Institute of Neurobiology and Molecular Medicine, Consiglio Nazionale delle Ricerche, Rome, Italy, January 10, 2005 (received for review December 17, 2004)

Abstract

Nerve growth factor (NGF) delivery to the brain of patients appears to be an emerging potential therapeutic approach to neurodegenerative disease, such as Alzheimer's disease (AD). The intranasal route of administration could provide an alternative to intracere-broventricular infusion and gene therapy. We previously showed that intranasal administration of NGF determined an amelioration of cholinergic deficit and a decrease in the number of phosphotau-positive neurons and of β-amyloid accumulation in AD11 mice, which express transgenic antibodies neutralizing NGF action and exhibit a progressive Alzheimer-like neurodegeneration. In this study, we report that the Alzheimer-like neurodegeneration in AD11 mice is linked to progressive behavioral deficits in visual recognition memory and spatial memory starting from 4 months of age. To establish whether intranasal administration of NGF, started after the appearance of the first memory deficits, could revert the cognitive deficits in AD11 mice, we assessed the performance of NGF-treated or control AD11 mice in the object recognition test and in a test of memory for place and context. Deficits exhibited by untreated AD11 mice could be rescued by the intranasal administration of NGF. Thus, this route of administration provides a promising way to deliver NGF to the brain in a therapeutic perspective.

Footnotes

↵ ** To whom correspondence should be addressed. E-mail: cattaneo{at}sissa.it.
Author contributions: R.D.R., A.A.G., and N.B. designed research; R.D.R., A.A.G., and C.B. performed research; L.M. contributed new reagents/analytic tools; R.D.R., A.A.G., S.C., N.B., and A.C. analyzed data; and R.D.R., A.A.G., S.C., N.B., and A.C. wrote the paper.
Abbreviations: NGF, nerve growth factor; BFCN, basal forebrain cholinergic neuron; AD, Alzheimer's disease; ORT, object recognition test; vORT, visual ORT; MWM, Morris water maze; OLT, object location test; OCT, object context test; DI, discrimination index.