Neuroscience Lecture

The Linda & Jack Gill Center for Biomolecular Science and The Program in Neuroscience are pleased to present the following talk:

Hui-Chen Lu, Ph.D.
Baylor College of Medicine

"Are the Wallerian Slow and NMNAT proteins neuroprotective in a mouse model of Alzheimer's disease?"

Wednesday, April 7, 2010
4:00 p.m.
Psychological & Brain Sciences Building
Room PY 101
IUB

Abstract: The loss of neurons, or neurodegeneration, is one of the hallmarks of Alzheimer’s disease (AD). Strategies to slow neurodegeneration may be effective in treating AD. Wallerian Slow (WldS) mice show reduced axonal loss in response to peripheral nerve injury and other neurodegenerative processes. These protective effects are attributed to a chimeric gene, Ube4b/Nmnat (WldS), which contains the entire coding region of Nicotinamide Mononucleotide Adenylyltransferase (NMNAT), leading to increased NMNAT expression. NMNAT is an NAD synthesizing enzyme and is broadly protective against neurodegeneration as first demonstrated in Drosophila. In these studies we have investigated if WldS and NMNAT are protective in mouse models of AD. A missense mutation in tau (tauP301L) induces the development of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). The age-related loss of neurons and cognitive dysfunction in rTg(tauP301L)4510 mice (designated Tau mice here for simplicity) closely mimics the clinical features of tauopathy. Thus, this transgenic mouse line is a useful animal model to study therapies for both AD- and tauopathy-associated neurodegeneration.

In my talk, I will present in vivo evidence that WldS and NMNAT are neuroprotective in aged Tau mice. Initially, we over-expressed WldS globally in the brains of Tau mice by crossing WldS mice with Tau mice to generate mice over-expressing both Tau and WldS. We next engineered recombinant adeno-associated viruses encoding WldS or only NMNAT and used them as “gene therapy” tools to over-express WldS or NMNAT in a tissue- and time-specific manner. These viral vectors allowed us to examine if WldS or NMNAT can prevent or rescue the Tau-related neurodegenerative phenotype after the onset of neurodegeneration. The efficacy of WldS and NMNAT was evaluated with a combination of anatomical, electrophysiological, and behavioral approaches. The neuroprotection offered by WldS and NMNAT at both the anatomical and functional level in treating the mouse model of Alzheimer’s disease will be discussed.