Mitochondria and synapse crosstalk in AD circuit vulnerability

About This Grant

PROJECT SUMMARY/ABSTRACT The rising prevalence of Alzheimer's Disease (AD) poses a significant challenge for human health. Characterized by progressive memory loss and cognitive decline, the long-term care costs for AD patients in the U.S. is expected to reach a trillion dollars by 2050. Despite decades of clinical research, there are few FDA-approved drugs to treat or prevent AD. Thus, a greater understanding of the mechanisms contributing to AD memory loss are needed to identify promising therapeutic targets. The entorhinal cortex (EC) is an initial site of tau and amyloid pathology in Alzheimer's patients and AD model mice. The major EC output is to the hippocampus, and EC-hippocampus synapse loss is a presumed cause of early memory impairment in AD. However, the molecular basis of EC circuit vulnerability is unknown. Along with synapse loss, mitochondrial dysfunction is an early pathological feature of AD. Because mitochondria provide fuel and metabolites vital for synapse function, restoring mitochondria and thereby synapse function may prevent or delay AD progression. Hippocampal CA2 mitochondria in ECII-contacting distal dendrites are larger than mitochondria in ECIII- contacting CA1 distal dendrites. Further, the mitochondrial calcium uniporter (MCU) is enriched in dendritic mitochondria near ECII-CA2, but not ECIII-CA1, synapses. Because excessive mitochondrial calcium is a proposed driver of AD pathology, we hypothesize that ECII-CA2 mitochondria and synapses are more vulnerable to AD pathology due to excess dendritic MCU-mediated calcium uptake. The ECII-CA2 synapse has yet to be investigated in the context of AD, and its distinct mitochondrial population is an ideal model to study the crosstalk between dendritic mitochondria and synapse function in the context of dysregulated mitochondrial calcium signaling in AD. In this Next Generation R03 proposal, we use acute slices from control and amyloid-based AD model mice to directly compare mitochondrial calcium uptake and mitochondrial fragmentation in EC-contacting CA2 and CA1 dendrites (Aim 1) as well as ECII-CA2 and ECIII-CA1 synapse function when mitochondrial calcium uptake is blocked (Aim 2). Results from these aims will reveal whether MCU-enriched dendritic mitochondria confer EC circuit vulnerability in an amyloid-based AD model. A new AD research program based on the outcome of this pilot study will identify the upstream mechanisms underlying dysregulated mitochondrial calcium signaling as well as the downstream consequences on mitochondria products and synaptic receptors essential for synapse function in amyloid- and tau-based AD models.