Intranasal “painless” Human Nerve Growth Factors Slows Amyloid Neurodegeneration and Prevents Memory Deficits in App X PS1 Mice

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.

Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer’s disease

“…Furthermore, AD mice receiving intranasal administrations of IGF-1 [64], insulin [8], NGF [65] or S14G-Humanin [66] exhibit substantially improved cognitive function. In addition, we previously demonstrated that the intranasal administration of SHED-CM reduced the neurological deficits in a rat model of focal cerebral ischemia [34].…”

Intranasal gene delivery for treating Parkinson’s disease: overcoming the blood–brain barrier

“…Peptides, proteins, trophic factors Insulin [17] Alzheimer's disease [37][38][39][40] Psychosocial stress [41] IGF-1 [7] Huntington's disease [176] Hypoxic Ischemia [177,178] LPS-induced brain injury [179] b-IFN [8,18] --BDNF [19] Ischemia [67] GDNF [12] Parkinson's disease [30] NGF [20,21] Alzheimer's disease [76,77] TBI [78][79][80] Ischemia [81,82] Oxytocin --Aggression [53] Autism [47][48][49]58,180] Self-perception [50] Stress [52] Schizophrenia [55][56][57] Alcohol withdrawal [54] NAP [25] Alzheimer's disease [25,84,85] Mild cognitive impairment [86] Hypobaric hypoxia [87] Osteopontin [23,24] Ischemic stroke [23] Hemorrhagic stroke [24] Orexins [90] Narcolepsy [91][92][93] Olfactory dysfunction [94] NPY...…”

“…Intranasal NGF has been most heavily investigated as a therapeutic strategy for mild cognitive impairment and Alzheimer's disease. For instance, intranasal NGF completely rescued memory impairment in mouse models of Alzheimer's disease [76,77], increased the number of choline acetyltransferase-positive neurons, and decreased phospho-tau-positive neurons, b-amyloid-positive neurites and plaque load [77].…”

Growth factor signaling and memory formation: temporal and spatial integration of a molecular network

“…Similarly, Conner et al (2009) found that septal NGF was required for hippocampal LTP and LTM. Interestingly, cholinergic cells are highly susceptible to Alzheimer's disease (AD) pathology (Auld et al 2002;Mesulam 2004), and NGF has been used as a successful therapy in aged rodents and an AD model (Fischer et al 1987(Fischer et al , 1991Backman et al 1996;Frick et al 1997;Capsoni et al 2012). NGF effects in young adult rodents is conflicting (Van der Zee et al 1995;Backman et al 1996;Muller et al 2012), indicating that the therapeutic effects of NGF may only be exerted in impaired states (Fischer et al 1991;Janis et al 1995;Backman et al 1996) and may actually impair memory in the absence of pathology (Backman et al 1996).…”