Abstract
The neurotrophin Nerve Growth Factor (NGF) holds a great potential as a therapeutic candidate for the treatment of neurological diseases. However, its safe and effective delivery to the brain is limited by the fact that NGF needs to be selectively targeted to the brain, to avoid severe side effects such as pain and to bypass the blood brain barrier. In this perspective, we will summarize the different approaches that have been used, or are currently applied, to deliver NGF to the brain, during preclinical and clinical trials to develop NGF as a therapeutic drug for Alzheimer’s disease. We will focus on the intranasal delivery of NGF, an approach that is used to deliver proteins to the brain in a non-invasive, safe, and effective manner minimizing systemic exposure. We will also describe the main experimental facts related to the effective intranasal delivery of a mutant form of NGF [painless NGF, human nerve growth factor painless (hNGFp)] in mouse models of Alzheimer’s disease and compare it to other ways to deliver NGF to the brain. We will also report new data on the application of intranasal delivery of hNGFp in Down Syndrome mouse model. These new data extend the therapeutic potential of hNGFp for the treatment of the dementia that is progressively associated to Down Syndrome. In conclusion, we will show how this approach can be a promising strategy and a potential solution for other unmet medical needs of safely and effectively delivering this neuroprotective neurotrophin to the brain.
Highlights
The neurotrophin Nerve Growth Factor (NGF) (Levi-Montalcini, 1952) has been suggested to play a neuroprotective factor in several neurological diseases and has been a matter of numerous basic and clinical research studies.Nerve growth factor is produced from a gene located on chromosome 1 (Francke et al, 1983) as a precursor proNGF which exists in two distinct isoforms of 27 and 35 kDa (Edwards et al, 1988)
We found that microglia are the first cellular target of human nerve growth factor painless (hNGFp), being the only cellular type, beside Basal forebrain cholinergic neurons (BFCNs), which express TrkA in 5xFAD mice
From the data described in this perspective paper, we conclude that the links between deficits or alterations in the NGF system and Alzheimer’s disease (AD) go well beyond the long-established neurotrophic actions of NGF on BFCNs
Summary
The neurotrophin Nerve Growth Factor (NGF) (Levi-Montalcini, 1952) has been suggested to play a neuroprotective factor in several neurological diseases and has been a matter of numerous basic and clinical research studies. A second paper in which the treatment was performed in 5xFAD mice allowed us to uncover the neuroprotective mechanisms through which hNGFp acts to reduce the neurodegeneration and to compare the effectiveness of intranasal delivery vs a local delivery to cholinergic neurons, mimicking the approach used in clinical trials (Capsoni et al, 2017). The fact that microglia is a target cell of NGF in the brain (Rizzi et al, 2018) and that is a primary target of intranasal hNGFp in the 5xFAD Alzheimer’s model (Capsoni et al, 2017) suggests that the microglia-mediated broad neuroprotective actions of hNGFp might be exploited in other disease states, in addition to AD We tested this hypothesis by investigating the efficacy of hNGFp in a mouse model of Down Syndrome (DS). We found that hNGFp treatment rescues astrogliosis, dystrophic microglia and neurogenesis deficits in the brain of 4 months old TS65Dn mice
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