Abstract
Nerve Growth Factor (NGF) is being considered as a therapeutic candidate for Alzheimer's disease (AD) treatment but the clinical application is hindered by its potent pro-nociceptive activity. Thus, to reduce systemic exposure that would induce pain, in recent clinical studies NGF was administered through an invasive intracerebral gene-therapy approach. Our group demonstrated the feasibility of a non-invasive intranasal delivery of NGF in a mouse model of neurodegeneration. NGF therapeutic window could be further increased if its nociceptive effects could be avoided altogether. In this study we exploit forms of NGF, mutated at residue R100, inspired by the human genetic disease HSAN V (Hereditary Sensory Autonomic Neuropathy Type V), which would allow increasing the dose of NGF without triggering pain. We show that "painless" hNGF displays full neurotrophic and anti-amyloidogenic activities in neuronal cultures, and a reduced nociceptive activity in vivo. When administered intranasally to APPxPS1 mice ( n = 8), hNGFP61S/R100E prevents the progress of neurodegeneration and of behavioral deficits. These results demonstrate the in vivo neuroprotective and anti-amyloidogenic properties of hNGFR100 mutants and provide a rational basis for the development of "painless" hNGF variants as a new generation of therapeutics for neurodegenerative diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Intranasal
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Alzheimer Disease / drug therapy
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Alzheimer Disease / metabolism
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Alzheimer Disease / pathology
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Alzheimer Disease / physiopathology
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Amyloid / metabolism*
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Animals
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Behavior, Animal / drug effects
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Behavior, Animal / physiology
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Cell Differentiation / drug effects
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Cell Proliferation / drug effects
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Cell Survival / drug effects
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Disease Progression*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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JNK Mitogen-Activated Protein Kinases / metabolism
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Learning / drug effects
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Learning / physiology
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Male
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Memory Disorders / prevention & control*
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Mice
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Mice, Transgenic
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Models, Molecular
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Mutation
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Nerve Growth Factor / administration & dosage*
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Nerve Growth Factor / adverse effects
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Nerve Growth Factor / genetics
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Nerve Growth Factor / pharmacology*
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Neurodegenerative Diseases / drug therapy*
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Neurodegenerative Diseases / metabolism
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Neurodegenerative Diseases / pathology
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Neurodegenerative Diseases / physiopathology
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Neurons / drug effects
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Neurons / pathology
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Neuroprotective Agents / administration & dosage
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Neuroprotective Agents / adverse effects
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Neuroprotective Agents / pharmacology
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Nociception / drug effects*
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Phospholipase C gamma / metabolism
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Protein Multimerization
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Protein Structure, Quaternary
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Receptor, trkA / metabolism
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Signal Transduction / drug effects
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Synaptophysin / metabolism
Substances
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Amyloid
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Neuroprotective Agents
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Synaptophysin
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Nerve Growth Factor
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Receptor, trkA
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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Phospholipase C gamma