Projects
- Spinal Cord Injury
- Alzheimer's Disease
- Neural Plasticity
The Aging and Alzheimer’s Disease Research Group in the Center for Neural Repair studies degenerative changes in the brain that are a consequence of both normal aging and pathological disorders such as Alzheimer’s disease. We explore the hypothesis that nervous system growth factors, including Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), and other trophic molecules influence neuronal survival and function at molecular, cellular, electrophysiological and behavioral levels. These programs contribute to our understanding of mechanisms underlying neuronal vulnerability to degeneration, and represent translational programs for developing more effective therapies for neurodegenerative disorders.
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. These findings led us to examine the hypothesis that NGF gene therapy would delay or even prevent degeneration of cholinergic neurons in the basal forebrain of patients with Alzheimer’s disease. In 2001, we initiated a program of NGF gene transfer to humans with Alzheimer’s disease, the first human clinical trial of gene therapy in an adult neurological disorder. This work has continued through Phase 2, multicenter human clinical trials. Preliminary results demonstrate that gene therapy results in elevated NGF expression in neurons near the targeted site (Figure 1)2.
Our current studies focus on Brain-derived Neurotrophic Factor (BDNF). BDNF play a major role in learning, memory, and regulation of synaptic plasticity in the cerebral cortex. In early Alzheimer’s disease, the entorhinal cortex exhibits neuron death that may contribute to loss of memory. We found that BDNF treatment in the entorhinal cortex can improve learning, reduce synapse loss, prevent neurodegeneration, and normalize gene expression in different models of AD (Figure 2)3,4. We are currently working to translate these promising findings to a first-in-human clinical trial using MRI-guided infusion of BDNF gene therapy targeting the entorhinal cortex (Figure 3).
At a more basic level, we are attempting to discover genes that correlate with risk to neurodegeneration as a function of normal aging, and how growth factors modify age-related changes in gene expression. We are further defining how normal aging influences neuronal structure at the level of dendritic spine density and morphology, and the impact of growth factors on these degenerative changes.
Figure 3. Widespread elevation of BDNF immunolabeling in the hippocampus following AAV2-BDNF delivery to entorhinal cortex of non-human primate. BDNF immunoreactivity in a control subject (A) and treated subject (B); arrow indicate area of elevated BDNF. (C) Fluorescent labeling illustrates BDNF immunoreactive fibers in the outer molecular layer (OML) and not in the inner molecular layer (IML) or granule cell layer (GC) of hippocampus. Scale bar a,b 1 mm; c 200 µm.