Cryptic exon incorporation occurs in Alzheimer's brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43.

摘要: Abnormal accumulation of TDP-43 into cytoplasmic or nuclear inclusions with accompanying clearance, a common pathology initially identified in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), has also been found Alzheimer’ disease (AD). serves as splicing repressor nonconserved cryptic exons that such function is compromised brains ALS FTD patients, suggesting clearance underlies its inability to repress exons. However, whether aggregates are prerequisite for the incorporation not known. Here, we assessed hippocampal tissues from 34 human postmortem including cases confirmed diagnosis AD neuropathologic changes along age-matched controls. We exon occurred all exhibiting pathology. Furthermore, was observed hippocampus when restricted only amygdala, earliest stage progression. Importantly, could be detected lacking inclusion but TDP-43. These data supports notion functional consequence depletion determined by likely occurs an early event proteinopathy may have greater contribution pathogenesis than currently appreciated. Early detection effective repression patients offer important diagnostic therapeutic implications this devastating illness elderly.