Rick Livesey, from the Gurdon Institute, provided insights into mechanisms of Alzheimer’s disease (AD) pathogenesis using human stem cell models (Shi et al., 2012). The cellular hallmarks of AD are the accumulation of amyloid precursor protein (APP) protein-derived Aβ peptide fragments and neurofibrillary tangles of the microtubule-associated protein tau. Livesey described the characterization of hiPSC neurons derived from patients with different familial AD mutations in the APP gene or Presenilin1 (PSEN1), the enzymatic subunit of the γ-secretase complex that processes APP. All of the different mutations increased the release of pathogenic longer forms of Aβ peptides. However, while increased APP gene dosage and APP mutations all increased total and phosphorylated tau in neurons, PSEN1 mutations did not (Moore et al., 2015). Manipulating γ-secretase activity in human neurons, using available drugs, identified that APP processing is linked to regulating levels of tau protein, hinting that extracellular Aβ may not be the only process relevant to disease pathogenesis. His work proposes a cell-autonomous link between APP processing and tau.
