A study reveals that some mutations in blood stem cells might help protect against late-onset Alzheimer’s disease. A team led by researchers at Baylor College of Medicine discovered that both a mouse model and people carrying blood stem cells with mutations in the gene TET2, but not in the gene DNMT3A, had a lower risk for developing Alzheimer’s disease. Their study proposes a mechanism that can protect against the disease and opens new avenues for potential strategies to control the emergence and progression of this devastating condition.

A new preclinical study has identified a mutant kinase that is connected to a genetic form of Alzheimer’s disease. By defining the mechanisms that drive the abnormal localization and signaling of the kinase, the findings could inform future research into new therapeutic strategies for the disorder, write study authors Maria Gauron and colleagues. Alzheimer’s disease is the most common form of dementia in older adults. Its incidence is rapidly increasing, but patients still lack effective therapies. Previous research has identified mutations in several genes that contribute to the early onset of Alzheimer’s disease, or to a higher risk of developing the condition. Now, Gauron et al. have added another gene to this list. The authors first performed a genome-wide analysis of families afflicted with Alzheimer’s disease. This analysis connected a higher incidence to homozygous carriers of a single nucleotide polymorphism (SNP) – a type of mutation – in a protein-coding region of the gene PRKCH. This SNP was tightly associated with a missense mutation that changed a single amino acid in the encoded protein, the kinase PKCη. Biochemical analysis revealed no differences in the mutant kinase’s regulation or in its ability to interact with and biochemically modify its substrates in isolation. However, the researchers observed a stark difference in behavior when they expressed mutant PKCη in cells. PKCη is normally found throughout the cytoplasm of a cell, but this disease-linked mutant (K56R) was found abundantly at the Golgi apparatus, an organelle within the cytoplasm. Its enzymatic activity was likewise concentrated at the Golgi, creating a gain of function in its activity at the Golgi but a loss of function elsewhere. This mislocalization was potentially due to stronger interactions between the mutant kinase and Golgi-associated proteins. “Our results also support previous studies demonstrating a role for altered PKC signal activity in [Alzheimer’s disease] pathogenesis,” Gauron et al. write.