Alan Nagahara, Ph.D.
Specialist, Senior Scientist
Previous work in the laboratory demonstrated that Nerve Growth Factor (NGF) gene therapy can prevent cholinergic neuronal loss and augment cholinergic function in experimental animal models1. Subsequently, these findings have led to clinical trials to examine NGF gene therapy in patients with Alzheimer’s disease (AD) to delay or even prevent degeneration of cholinergic neurons in the basal forebrain. Preliminary results demonstrate that gene therapy results in elevated NGF expression in neurons near the targeted site (Figure 1)2.
Our current studies focuses on another neurotrophin called Brain-derived Neurotrophic Factor (BDNF). BDNF play a major role in the brain that is important for learning and memory and regulating synaptic plasticity in the hippocampus and cortical regions. In the initial stages of AD, the entorhinal cortex exhibits neuropathology and cell loss that is thought to contribute to the early memory loss in AD patients. Our studies have demonstrated that BDNF treatment in the entorhinal cortex can improve learning, reduce the loss of synaptic connection, prevent cell loss, and normalize gene expression in different models of AD (Figure 2)3,4. Another project of the BDNF Program is development of using MRI guidance to accurately target the entorhinal cortex in collaboration with Dr. Bankiewicz at the UCSF for use in clinical trials with AD patients. Our BDNF Program is also interested in developing small molecules of BDNF and using combinatorial treatment of BDNF with a treatment directed at reducing beta amyloid. These BDNF projects provide potential therapy for the treating AD and other neurodegenerative diseases.
1. Nagahara A.H., Wilson B.R., Ivasyk I., Kovacs I., Rawalji S., Bringas J.R., Pivirotto P.J., Sebastian W.S., Samaranch L., Bankiewicz K.S., & Tuszynski M.H. MR-guided delivery of AAV2-BDNF into the entorhinal cortex of non-human primates. Gene Ther. (2018) Mar 13 EPub.
2. Tuszynski, M.H., Yang, J.H., Barba, D., U, H.S., Bakay, R.A., Pay, M.M., Masliah, E., Conner, J.M., Kobalka, P., Roy, S. & Nagahara, A.H. Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurol 72, 1139-1147 (2015).
3. Nagahara, A.H., Mateling, M., Kovacs, I., Wang, L., Eggert, S., Rockenstein, E., Koo, E.H., Masliah, E. & Tuszynski, M.H. Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice. J Neurosci 33, 15596-15602 (2013).
4. Nagahara, A.H. & Tuszynski, M.H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10, 209-219 (2011).
5. Nagahara, A.H.
, Merrill, D.A., Coppola, G., Tsukada, S., Schroeder, B.E., Shaked, G.M., Wang, L., Blesch, A., Kim, A., Conner, J.M., Rockenstein, E., Chao, M.V., Koo, E.H., Geschwind, D., Masliah, E., Chiba, A.A. & Tuszynski, M.H. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med 15
, 331-337 (2009).