Neurotrophic factor therapies utilize endogenous proteins that support neuron survival, function, and plasticity to treat neurodegenerative diseases. These growth factors represent a disease-modifying approach rather than just symptomatic treatment["@nagahara2011"]. The neurotrophic factor family includes several key proteins that have been extensively studied for their neuroprotective properties, including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and insulin-like growth factor (IGF-1)[@hefti2008].
The rationale for neurotrophic factor therapy stems from the observation that many neurodegenerative diseases are characterized by decreased levels of endogenous neurotrophins or impaired signaling through their receptors. For example, BDNF levels are reduced in Alzheimer's disease brains, and GDNF expression is altered in Parkinson's disease. Restoring or enhancing neurotrophic support represents a logical therapeutic strategy to slow or halt disease progression["@holtman2022"].
Molecular Biology of Neurotrophic Factors
Neurotrophin Family
The neurotrophin family comprises four structurally related proteins that signal through the Trk family of receptor tyrosine kinases and the p75NTR pan-neurotrophin receptor:
Brain-Derived Neurotrophic Factor (BDNF)
Gene: BDNF located on chromosome 11p14.1
Protein: 119 amino acid mature protein, processed from pro-BDNF
Receptors: TrkB (primary), p75NTR (secondary)
Expression: Highly expressed in [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cortex), basal forebrain
[GDNF Family Ligands - NCBI Gene](https://www.ncbi.nlm.nih.gov/gene/2698)
[Neurotrophic Factors in CNS Disorders - Nature Reviews](https://www.nature.com/subjects/neurotrophic-factors)
References
[Unknown, Nagahara AH, Tuszynski MH. Potential therapeutic uses of neurotrophic factors in CNS disorders. Nat Rev Neurol. 2011;7(1):39-50 (2011)](https://pubmed.ncbi.nlm.nih.gov/22019408/)
[Unknown, Hefti FF. Development of effective therapy for Alzheimer's disease based on neurotrophic factors. Neurochem Res. 2008;33(12):2435-2444 (2008)](https://pubmed.ncbi.nlm.nih.gov/18554090/)
[Holtman IR, Chao JR, Heurtin C, et al., Neurotrophic factors in neurodegenerative disease. Nat Rev Drug Discov. 2022;21(7):477-498 (2022)](https://pubmed.ncbi.nlm.nih.gov/35641725/)
[Unknown, Peng S, Wuu J, Mufson EJ, Fahnestock M. Increased proBDNF and reduced mature BDNF in prefrontal cortex in Alzheimer's disease. J Alzheimers Dis. 2020;76(3):1045-1058 (2020)](https://pubmed.ncbi.nlm.nih.gov/32651324/)
[Nagahara AH, Merrill DA, Coppola G, et al., Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med. 2009;15(3):331-337 (2009)](https://pubmed.ncbi.nlm.nih.gov/19198614/)
[Tuszynski MH, Thal L, Pay M, et al., A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med. 2005;11(5):551-555 (2005)](https://pubmed.ncbi.nlm.nih.gov/15864417/)
[Rafii MS, Tuszynski MH, Thomas RG, et al., Adeno-associated virus delivery of nerve growth factor for Alzheimer disease: A randomized clinical trial. JAMA Neurol. 2023;80(9):958-966 (2023)](https://pubmed.ncbi.nlm.nih.gov/37466947/)
[Gill SS, Patel NK, Hotton GR, et al., Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003;9(5):589-595 (2003)](https://pubmed.ncbi.nlm.nih.gov/12668533/)
[Lang AE, Gill S, Patel N, et al., Randomized controlled trial of intraputamenal GDNF infusion in Parkinson disease. Arch Neurol. 2006;63(7):978-985 (2006)](https://pubmed.ncbi.nlm.nih.gov/16831921/)
[Zuccato C, Tartari M, Crotti A, et al., Huntingtin interacts with REST/NRSF to modulate the expression of genes. Nat Genet. 2010;42(3):245-254 (2010)](https://pubmed.ncbi.nlm.nih.gov/20157542/)