Fellowship for Jamal Williams: Exploration of a Novel Therapeutic for Alzheimer's Disease and Related Disorders

“Exploration of a Novel Therapeutic for Alzheimer’s Disease and Related Disorders” Project Summary / Abstract Neurodegenerative disorders are responsible for progressive loss of synaptic function that is accompanied by cognitive decline. The mechanisms in which pathological hallmarks of these diseases influence the functioning of cognitive processes such as memory recognition, planning, and decision making, is a major focus for therapeutic research. In Alzheimer’s disease (AD), the primary pathological marker thought to be most closely linked to cognitive dysfunction is neurofibrillary tangles (NFTs), which are comprised of pathogenic aggregates of hyperphosphorylated tau. To better understand the pathophysiological relationship between synaptic loss and cognitive dysfunction in a tau model for AD and related disorders (ADRD), the transgenic mouse model P301S which overexpresses hyperphosphorylated tau was employed for this project. Work done during my predoctoral studies revealed a decline of proper spatial and short-term recognition memory that is accompanied by the progressive loss of the glutamatergic receptor NMDAR and NMDAR transmission in prefrontal cortex (Aim 1). It is suspected that maladaptive pathophysiological mechanisms associated with the onset of NFTs are responsible for synaptic and cognitive dysfunction. An area of interest is the ubiquitin-proteasome system (UPS), a clearance mechanism responsible for protein degradation in the cell. Defective protein clearance has been implemented in AD, however the role in which the UPS relates to tau-induced cognitive decline has yet to be elucidated. Further preliminary data identified the upregulation of an E3 ubiquitin ligase to be responsible abnormal degradation of NMDARs. In Aim 2 I will determine if selectively knocking down this E3 ubiquitin ligase in PFC of P301S mice through in vivo gene transfer will rescue synaptic and cognitive dysfunction. This will be assessed through cognitive behavioral assays, biochemical and immunocytochemical detection of synaptic proteins, and electrophysiological recordings. These highly transferable skills will allow me to transition into a postdoctoral appointment, where I aim to study how epigenetic enzymes direct chromosomal architecture, causing downstream changes in gene expression seen in neurodegenerative disorders (Aim 3). My long-term goal is to obtain a faculty position at a research-intensive institution where I will combine a multifaceted approach in understanding how the spatial organization of chromatin can lead to neurobiological and neurodegenerative etiologies.