Stem Cell Models of Dementia

We have established a dermal fibroblast bank containing cell lines from research participants in the Knight ADRC who carry disease mutations (GRN, MAPT, APP, PSEN1, PSEN2), risk variants (APOE, PLD3, TREM2, UNC5C) and unrelated controls to serve as a resource for studying the mechanisms underlying dementias. We have reprogrammed a subset of these cells into induced pluripotent stem cells (iPSC). Human iPSC are self-renewing cells with the capacity to form cells in any of the three germ layers. We have developed a protocol for robust and efficient generation of several neuronal and glial subtypes using these iPSC. Additionally, we are exploiting CRISPR/Cas9 to further engineer human iPSC to answer fundamental questions related to Alzheimer’s disease and other tauopathies.

 

The Effects of MAPT Mutations on Tau Metabolism

Dominantly inherited mutations in microtubule associated protein tau (MAPT) cause familial forms of frontotemporal dementia (FTD). While several mechanisms have been proposed to explain how mutations in the MAPT gene contribute to disease, the basic mechanism by which MAPT mutations causes FTD remains poorly understood. We are investigating the effects of MAPT mutations in human stem cell models on tau stability, phosphorylation, cleavage and aggregation.

 

Phospholipase D3 (PLD3)

PLD3 was recently identified as an AD risk gene. We hypothesize that PLD3 impacts AD risk by influencing APP and Aβ in a γ-secretase-dependent and –independent manner. We are using immortalized, stem cell and mouse models to investigate the normal function of PLD3 and its role in AD pathogenesis.

 

Functional Characterization of Disease Mutations and Risk Variants Associated with Dementia

In collaboration with the Cruchaga Lab, we use cell-based assays to characterize the functional affects of disease mutations and risk variants in known and novel genes.