The focus of Dr. Albers’ laboratory is to gain a mechanistic understanding of early pathogenic processes of neurodegenerative diseases that are modifiable or reversible. Using mouse genetics, his lab has specifically tailored olfactory neurons to express disease genes associated with Alzheimer’s disease in a reversible manner, such that the disease gene can be turned off by feeding the mice a low-dose antibiotic. Patients with Alzheimer’s disease and Parkinson’s disease suffer olfactory deficits early in the course of their disease, pointing to a particular susceptibility of this neural circuit to the pathogenesis of these diseases, and making the olfactory system a logical starting point. Moreover, the olfactory neural circuit is one of the best-understood neural circuits in the mammalian brain. Characterization of this mouse model has uncovered a novel action of an Alzheimer’s disease gene – expression of this gene in less than 1% of the primary olfactory neurons is sufficient to cause olfactory deficits in behavioral assays. Reversal of the disease gene expression affects a complete recovery of the behavioral deficit in adult mice.
The generous support from the Rappaport Family Fund afforded Dr. Albers’ team the opportunity to learn that olfactory neurons are dying at an accelerated rate when the disease gene is expressed. This is the first mouse neuron population shown to be susceptible to this disease gene. This advance has generated exciting studies that delve into the molecular mechanisms leading to accelerated neuronal death and to develop a system to screen for molecules that interfere with this neurodegenerative process. Insights gained from these studies may contribute to the development of an effective therapy for these devastating diseases. The funds provided by the Rappaport Family helped support investigator salaries and defrayed costs associated with laboratory work, ultimately facilitating this important research. Dr. Albers’ findings will be published as well as presented at two international meetings.
The goal of the research in the Albers lab is to elucidate the pathogenic actions and physiological functions of genes implicated in neurodegenerative disease. Our principal hypothesis is that these genes confer vulnerability to neurons by disrupting the integrity of neurons and neural circuits. The questions addressed by these studies intersect with fundamental questions in neuroscience, including how are connections in the nervous system formed, how are these connections modified by experience, and how is the communication across these connections disrupted by disease mechanisms. We address these issues in the peripheral olfactory neural circuit of the mouse and human, a circuit that is evolutionarily conserved. The mouse circuit is genetically tractable, and the human circuit is vulnerable to neurodegenerative disease. We combine novel mouse models that express pathogenic and normal isoforms of the human amyloid precursor protein solely in a subset of olfactory neurons with multiphoton in vivo imaging, fluorescence activated cell sorting, deep sequencing, and other basic techniques of investigation. Examination of these lines has revealed miswiring of the olfactory neural circuit and profound changes in gene expression in neurons not expressing the disease gene, associated with accelerated neuronal turnover in vivo. A second focus of the laboratory is to elucidate the physiological function of these genes by generating and examining cell-specific knockouts of the gene family in specific classes of neurons in this circuit. We believe that some of the insights revealed in these investigations will provide clues to understanding the actions of these disease genes in other vulnerable, plastic circuits in the brain, such as the entorhinal cortex and the hippocampus.