The causes and mechanisms for neurodegeneration in Alzheimer?s Disease and other dementias are still not fully understood. While multiple mutations and risk factors have been identified, aging is still the top risk factor for these neurodegenerative diseases. One hypothesis states that synapse loss is the first step in the neurodegenerative cascade. It is necessary to understand how the presence of amyloid-beta peptides and plaques or tau tangles drives synapse loss, particularly in the context of aging. A significant hurdle to address this question is that dynamic, longitudinal studies to measure synaptic morphology, function, and plasticity, are unfeasible with humans or in mammalian models of Alzheimer?s Disease. In this project, we propose to use the model organism C. elegans to perform integrative analysis of synaptic health in animals expressing human amyloid-beta and tau. We will use high-throughput, high-content platforms to characterize the effects of these insults in synaptic morphology, connectivity, and function as animals age. In addition, we will survey neurons of different types to determine whether these exhibit different degrees of vulnerability. The findings from this work will be the stepping stone to future work to perform high-throughput screens to identify the neurodegeneration network, and to build mechanistic insights in the synapse degeneration process.
The proposed work will identify key components in synaptic degeneration as a result of entities typically associated with Alzheimer?s Disease (amyloid-beta and tau). By characterizing the neuron types and conditions upon which synapse degeneration is triggered, future work will enable understanding the mechanisms of synaptic decline in Alzheimer?s disease. Translation of work can lead to finding successful therapies or prevention strategies.
| Saberi-Bosari, Sahand; Huayta, Javier; San-Miguel, Adriana (2018) A microfluidic platform for lifelong high-resolution and high throughput imaging of subtle aging phenotypes in C. elegans. Lab Chip 18:3090-3100 |
| San-Miguel, Adriana; Kurshan, Peri T; Crane, Matthew M et al. (2016) Deep phenotyping unveils hidden traits and genetic relations in subtle mutants. Nat Commun 7:12990 |
