Alan Nagahara, Ph.D.
Specialist, Senior Scientist
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.
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
1. Nagahara, A.H. & Tuszynski, M.H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov 10, 209-219 (2011).
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.
, 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).