Recent findings have revealed new mechanisms in neurons that cause Alzheimer’s disease. Specifically, researchers at the University of California San Diego have discovered changes that lead to neurons reverting to an earlier cell state.
Early-onset familial Alzheimer’s disease (EOFAD) is a dominantly inherited neurodegenerative disorder. It is caused by over 300 mutations in the PSEN1, PSEN2 and APP genes. The most common symptoms are the accumulation of misfolded β-amyloid (Aβ) in plaques and Tau aggregates in neurofibrillary tangles. These are associated with progressive memory loss and cognitive decline. Researchers have found that they are temporally accelerated manifestations of the more common sporadic late-onset AD (LOAD).
EOFAD-causing mutations are completely penetrant. This has enabled researchers to develop our understanding of AD. Nonetheless, the failure of pathology-targeting therapeutic developments suggests that the formation of plaques and tangles may be symptomatic and do not actually describe the aetiology of the disease.
In a study, published in Science Advances, researchers used an integrative, multiomics approach and systems-level analysis in human induced pluripotent stem cell (hiPSC)-derived neurons to generate a mechanistic disease model for EOFAD. They started with patient-specific cells from donors harbouring four unique mutations in PSEN1 and transformed them into neurons. They then utilised next-generation sequencing techniques to explore what genes were being expressed in these neurons and how gene expression was regulated. Finally, they compared these results to neurons of healthy individuals.
They found that EOFAD neurons dedifferentiated to a precursor-like state with signatures of ectoderm and nonectoderm lineages. RNA-seq, ATAC-seq, and ChIP-seq analysis also revealed that transcriptional alterations in the cellular state were orchestrated by changes in histone methylation and chromatin topology. Additionally, they demonstrated that these mechanisms were also observed in post-mortem human brain samples from patients with EOFAD. Thereby, validating their hiPSC-derived neuron models.
These altered cellular programs provide key insight into the underlying mechanistic basis for neurodegeneration in AD. It also offers a basis for innovative therapeutic intervention at an earlier stage of disease progression. The team are now working on developing drugs to inhibit these mechanisms.
Image credit: By Eraxion – canva.com