Leo Belluscio, PhD
Senior Investigator
Developmental Neural Plasticity Section
National Institute of Neurological Disorders and Stroke National Institutes of Health
(March 7, 2017)
Using the Olfactory System to Study Neurodegeneration
Many patients with Alzheimer’s disease may find that they have lost their sense of smell. This can occur very early in the course of the disease, perhaps even before problems with memory become noticeable. Dr. Belluscio has used a mouse model of Alzheimer’s disease to pinpoint the molecular basis of the loss of smell. His group has shown that by blocking a particular protein, olfactory neurons are able to recover, even after extensive damage. His future research will try to determine if the same process is present in human Alzheimer’s disease patients.
The regenerative ability of the mammalian olfactory system, combined with is its precisely defined anatomical maps, provides an ideal platform to study neural circuit disruption and repair.
We took advantage of this to develop an olfactory-based mouse model of Alzheimer’s disease (AD) that can be regulated in vivo through drug application. Our goal was to gain insight into the early loss of olfactory function that is commonly reported in AD patients.
Using this transgenic mouse model, we reversibly expressed a humanized mutant form of the Amyloid Precursor Protein (hAPP) in olfactory sensory neurons (OSNs) and revealed clear neural apoptosis in hAPP expressing neurons at a very early age. We further determined that by turning off hAPP expression after extensive degeneration had occurred the olfactory system is still capable of recovering both in its neural structure and function. Finally, we show that the observed OSN loss is through a cell-autonomous mechanism that may mark an early cellular phase of disease. Future studies will determine if similar transduction pathways mediate the olfactory loss in AD patients.