BLOG: Neurotrophins hold the key to unlock diseases of the brain, eye
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As a neuroscientist, biochemist and molecular biologist, I’m interested in the biosynthesis and regulation of neurotrophic factors, including nerve growth factor and brain-derived neurotrophic factor.
Nerve growth factor (NGF) is an important neurotrophic factor for the survival of axons —the nerve fibers that transmit electrical impulses away from the body of a nerve cell, or neuron — to communicate with other neurons, and brain derived neurotrophic factor (BDNF) is essential for brain plasticity, the process that allows the brain to continually make and break synapses.
Together, all the neurotrophic factors are a bit like food for the neurons. Every neuron in your body relies on them to provide survival factors and to regulate neuronal functioning in the brain, the eye and elsewhere.
A link between Alzheimer’s, glaucoma
Alzheimer’s disease, autism and glaucoma are all conditions in which the neurotrophins NGF and BDNF are dysregulated in some way. One of the Alzheimer’s disease-related phenomena we are studying in my lab is the loss of neuronal connections that happens before brain cells die. Neurons in the hippocampus region of the brain begin to lose BDNF. The loss of BDNF inhibits their connection with other neurons, disrupting connections among the basal forebrain, hippocampus and cortex that normally form a circuit for learning and memory.
BDNF and NGF maintain the integrity of connections between brain regions through axonal transport. As the neurotrophins travel up and down axons, they signal survival, maintaining the axons as they’re being transported along them. In much the same way, the transport of these neurotrophins along the optic nerve maintains the eye-brain connection. The similarity of the transport function allows us to use techniques from the study of Alzheimer’s disease to better understand glaucoma.
In a properly functioning eye, retinal ganglion cells (RGCs) obtain the neurotrophic factors they need from the brain via the optic nerve. But in a glaucomatous eye, the availability of neurotrophins is limited by the disease process; as the optic nerve degenerates, the neurotrophin highway to the retina shuts down, the RGCs become starved for the NGF and BDNF they need to function, lose their connection to the brain and die. Ultimately, it is the loss of RGCs that causes vision loss in glaucoma.
Therapeutic effects of neurotrophins
It would be nice if we could just inject some BDNF into the brain or the retina to fix these problems, but unfortunately it isn’t that simple. BDNF is a short-lived, unstable molecule that tends to get “stuck” to nearby receptors and fails to spread to more distant receptors. It’s also cytotoxic in larger doses and may harm neurons or cause seizures or other undesirable effects. Additionally, research has shown that if you repeatedly inject BDNF, it downregulates its own receptors, rendering further injections even less effective.
However, there has been some encouraging research in recent years surrounding neurotrophic factors as therapeutic targets for glaucoma. NGF is nontoxic, more stable than BDNF and easier to distribute in tissues. In fact, a recombinant form of NGF called Oxervate (cenegermin-bkbj, Dompé) is already approved in the U.S. and Europe as a therapy for corneal nerve damage, the underlying cause of neurotrophic keratitis.
Early-stage trials for the use of NGF to treat glaucoma are also underway. Intravitreal injections of antibodies and small-molecule agonists designed to activate BDNF receptors have also been tested in animal models of glaucoma and are progressing to human trials, which is exciting.
Finally, we know that lifestyle factors such as exercising regularly, eating a diet with lots of antioxidant-rich foods, getting enough sleep and avoiding stress all help to boost endogenous neurotrophic factors. A new exercise regimen probably won’t help much if a glaucoma patient’s RGCs have already been damaged and aren’t properly transporting BDNF, but over the long term, a healthy lifestyle is protective because it provides the neurotrophins that neurons need for survival and function.
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Margaret Fahnestock, PhD, is a professor in the department of psychiatry and behavioral neurosciences at McMaster University in Ontario, Canada. She is also an associate member of the department of biology and a member of the medical sciences graduate program. Her research is focused on neurotrophic factors, specifically understanding how neurotrophin gene expression, regulation, signaling and trafficking are dysregulated in Alzheimer’s disease and autism. She will be teaching a course on “Neurotrophins and their Receptors in Glaucoma” at the 2023 NORA conference on Brain-Based Rehabilitation. For more information and to register, visit https://noravisionrehab.org/about-nora/annual-conferences/2023-annual-conference.
Disclaimer: The views and opinions expressed in this blog are those of the authors and do not necessarily reflect the official policy or position of the Neuro-Optometric Rehabilitation Association unless otherwise noted. This blog is for informational purposes only and is not a substitute for the professional medical advice of a physician. NORA does not recommend or endorse any specific tests, physicians, products or procedures. For more of our online content, click here.
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