Alzheimer’s disease (AD), a prevalent, adult-onset, neurodegenerative disease, is clinically characterized by progressive impairments in cognition and memory. These clinical features are accompanied by characteristic histological changes in the brain, including neuronal loss, extracellular deposition of fibrillogenic Ab peptides in senile plaques and intracellular neurofibrillary tangles. The principal risk factors for AD are age and inheritance of mutant genes, or polymorphic alleles that predispose individuals to late-onset disease.
Over the past 20 years, my laboratory has focused on examining the cellular and molecular biology of the b-amyloid precursor protein (APP), or presenilins (PS1 and PS2), molecules that are mutated in pedigrees with autosomal dominant, familial forms of Alzheimer’s disease (FAD). The function(s) of APP in the central nervous system (CNS) are still not fully understood, but we have demonstrated that APP is subject to rapid anterograde axonal transport and subject to proteolytic processing at, or near, terminal fields. In collaboration with Robert Malinow at UCSD, we have also shown that synaptic activity modulates APP processing and Ab production, and that both axonal and dendritic release of these peptides alter spine dynamics and glutamatergic neurotransmission. Our current efforts are focused on clarifying the dynamics and regulation of APP trafficking and processing cultured neurons and hippocampal slices using recombinant lentiviral-driven APP-GFP chimeras and live cell imaging approaches. In order to assess the normal function of PS, we have used gene targeting strategies; PS1-deficient animals die in late embryogenesis due to defective Notch signaling that is in large part, the result of failed intramembranous, “g-secretase” processing of a membrane-bound Notch substrates. This “g-secretase” activity is also responsible for liberating Ab peptides from membrane-bound APP derivatives. We, and others, have provided genetic and biochemical evidence has revealed that PS associates with nicastrin (NCT), APH-1 and PEN-2 in high molecular weight complexes, and our current efforts are aimed at understanding the temporal assembly of these membrane proteins, the nature of subunit interactions and the enzymatic mechanism(s) by which the complex promotes “g-secretase” processing of Notch, APP and other type 1 membrane proteins.
A significant effort of our laboratory has been to develop and characterize transgenic animals that express FAD-linked variants of PS1 and APP to clarify the underlying biochemical and pathophysiological alterations that cause AD. We have exploited these animals, as well as animals in which we have conditionally inactivated PS, to clarify issues relevant to axonal trafficking of membrane proteins, neurodegeneration, neuronal vulnerability, gene expression and APP/Ab metabolism. A significant effort in our laboratory is focused on understanding the cell non-autonomous effects of FAD-linked mutant PS1 expression on hippocampal neurogenesis. Our future studies will focus heavily on the mechanisms that are responsible for the observed effects using temporal and system-specific conditional gene inactivation approaches. Extending our demonstration that enriched environments and exercise modulates Ab metabolism and deposition in vivo, our ongoing efforts are focused on the role of polypeptides encoded by genes that are selectively regulated in these settings. Finally, we have been exploring the impact of the microbiome in modulation of amyloid deposition in mouse models of AD.
In summary, my research program is designed to integrate genetic, neurobiologic, molecular and cellular information to clarify the normal biology of APP and PS and the mechanisms by which mutant genes cause AD. The value of animal models that recapitulate some features of the human disease have, and will be of enormous value for addressing issues relevant to the selective vulnerability of specific CNS systems, the pathophysiological sequelae and ultimately, will provide opportunities to explore mechanism-based therapeutic strategies.

shabana@uchicago.edu

My fascination for RNA world inspired me to address the influence of RNA tertiary structure on gene regulation for my doctoral studies and achieved my PhD in bio-chemistry from The University of Chicago. To leverage my expertise on RNA methodologies I have joined Sisodia lab as a post-doctoral researcher. Here, I would like to investigate the influence of gut microbiome in modulating microglial function in neurodegeneration in murine Alzheimer’s model by assessing the microglial RNA networks. Outside of research, I love reading, cooking (gut health !!!) and mentoring.

wnhan@uchicago.edu

nslimmo@uchicago.edu

I am a Research Technician in the Sisiodia Lab at the University of Chicago. One of my primary research interests is sex differences in the gut microbiota-mediated regulation of microglia in Alzheimer’s Disease (AD). In particular, I am intrigued by the role of hormonal influences in AD pathology and how this may lead to sex-specific therapeutic approaches in the future. Currently, I maintain the lab’s mouse colony and contribute to lab projects through PCR and Western Blot analysis, as well as harvesting and immunohistochemistry of tissue samples.

During my undergraduate at Washington University in St. Louis, I studied vestibular tuning, development, and locomotion in zebrafish under Dr. Martha Bagnall. In Dr. Sisodia’s lab, I hope to become acquainted with rodent models and expand my cellular and molecular biology skillset. Inspired by my passion for biomedical research, I would also like to eventually pursue a doctoral degree in neurobiology. In my free time, I enjoy running , DJing, keeping reptiles, and doing global health nonprofit work.

pblauth@uchicago.edu

I am a second-year in the College studying neuroscience. I am currently working as a research assistant alongside Piyali to understand further the hormonal importance of the gut-brain axis on Alzheimer’s Disease. Outside the lab, I am part of the water polo team, volunteer for the Red Cross, and attempt to learn Italian.

jmichalkiewicz@uchicago.edu

shaynacohen@uchicago.edu

kshi@uchicago.edu