2024-02-27 カリフォルニア大学サンタバーバラ校(UCSB)
<関連情報>
- https://news.ucsb.edu/2024/021375/untangling-sticky-mystery-researchers-make-precious-headway-genetic-form-alzheimers
- https://www.cell.com/neuron/abstract/S0896-6273(24)00093-X
アルツハイマー病は常染色体優性遺伝であることが一核RNA塩基配列解析で明らかになった Single-nucleus RNA sequencing demonstrates an autosomal dominant Alzheimer’s disease profile and possible mechanisms of disease protection
Maria Camila Almeida,Sarah J. Eger,Caroline He,…,Diego Sepulveda-Falla,Francisco Lopera,Kenneth S. Kosik
Neuron Published:February 27, 2024
DOI:https://doi.org/10.1016/j.neuron.2024.02.009
Highlights
•An autophagy gene profile distinguishes PSEN1-E280A ADAD cases from sporadic AD
•A possible mechanism for the PSEN1-E280A Christchurch variant effect observed
•Unique cellular responses in ADAD and sporadic AD may impact clinical trial design
Summary
Highly penetrant autosomal dominant Alzheimer’s disease (ADAD) comprises a distinct disease entity as compared to the far more prevalent form of AD in which common variants collectively contribute to risk. The downstream pathways that distinguish these AD forms in specific cell types have not been deeply explored. We compared single-nucleus transcriptomes among a set of 27 cases divided among PSEN1-E280A ADAD carriers, sporadic AD, and controls. Autophagy genes and chaperones clearly defined the PSEN1-E280A cases compared to sporadic AD. Spatial transcriptomics validated the activation of chaperone-mediated autophagy genes in PSEN1-E280A. The PSEN1-E280A case in which much of the brain was spared neurofibrillary pathology and harbored a homozygous APOE3-Christchurch variant revealed possible explanations for protection from AD pathology including overexpression of LRP1 in astrocytes, increased expression of FKBP1B, and decreased PSEN1 expression in neurons. The unique cellular responses in ADAD and sporadic AD require consideration when designing clinical trials.
Graphical abstract
