Cryptic exon incorporation occurs in Alzheimer's brain lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43.
Abnormal accumulation of TDP-43 into cytoplasmic or nuclear inclusions with accompanying nuclear clearance, a common pathology initially identified in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), has also been found in Alzheimer' disease (AD). TDP-43 serves as a splicing repressor of nonconserved cryptic exons and that such function is compromised in brains of ALS and FTD patients, suggesting that nuclear clearance of TDP-43 underlies its inability to repress cryptic exons. However, whether TDP-43 cytoplasmic aggregates are a prerequisite for the incorporation of cryptic exons is not known. Here, we assessed hippocampal tissues from 34 human postmortem brains including cases with confirmed diagnosis of AD neuropathologic changes along with age-matched controls. We found that cryptic exon incorporation occurred in all AD cases exhibiting TDP-43 pathology. Furthermore, incorporation of cryptic exons was observed in the hippocampus when TDP-43 inclusions was restricted only to the amygdala, the earliest stage of TDP-43 progression. Importantly, cryptic exon incorporation could be detected in AD brains lacking TDP-43 inclusion but exhibiting nuclear clearance of TDP-43. These data supports the notion that the functional consequence of nuclear depletion of TDP-43 as determined by cryptic exon incorporation likely occurs as an early event of TDP-43 proteinopathy and may have greater contribution to the pathogenesis of AD than currently appreciated. Early detection and effective repression of cryptic exons in AD patients may offer important diagnostic and therapeutic implications for this devastating illness of the elderly.
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Mingkuan
M
Sun
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
William
W
Bell
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Katherine D
KD
LaClair
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Jonathan P
JP
Ling
Department of Biology, Johns Hopkins University, Baltimore, MD, 21218, USA.
Heather
H
Han
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Yusuke
Y
Kageyama
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Olga
O
Pletnikova
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Juan C
JC
Troncoso
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. wong@jhmi.edu.|Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. wong@jhmi.edu.
Philip C
PC
Wong
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. lchen99@jhmi.edu.
Liam L
LL
Chen
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D057177:TDP-43 Proteinopathies / Q000378:metabolism / Q000473:pathology
D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human
ALS/FTD; Alzheimer’s disease; Cryptic exon; Hippocampal sclerosis; Neurodegeneration; TDP-43 proteinopathy