Dataset Information

Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies.

ABSTRACT: SRPK2 is abnormally activated in tauopathies including Alzheimer's disease (AD). SRPK2 is known to play an important role in pre-mRNA splicing by phosphorylating SR-splicing factors. Dysregulation of tau exon 10 pre-mRNA splicing causes pathological imbalances in 3R- and 4R-tau, leading to neurodegeneration; however, the role of SRPK2 in these processes remains unclear. Here we show that delta-secretase (also known as asparagine endopeptidase; AEP), which is activated in AD, cleaves SRPK2 and increases its nuclear translocation as well as kinase activity, augmenting exon 10 inclusion. Conversely, AEP-uncleavable SRPK2 N342A mutant increases exon 10 exclusion. Lentiviral expression of truncated SRPK2 increases 4R-tau isoforms and accelerates cognitive decline in htau mice. Uncleavable SRPK2 N342A expression improves synaptic functions and prevents spatial memory deficits in tau intronic mutant FTDP-17 transgenic mice. Hence, AEP mediates tau-splicing imbalance in tauopathies via cleaving SRPK2.

SUBMITTER: Wang ZH

PROVIDER: S-EPMC6279401 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies.

Wang Zhi-Hao ZH Liu Pai P Liu Xia X Yu Shan Ping SP Wang Jian-Zhi JZ Ye Keqiang K

The Journal of experimental medicine 20181029 12

SRPK2 is abnormally activated in tauopathies including Alzheimer's disease (AD). SRPK2 is known to play an important role in pre-mRNA splicing by phosphorylating SR-splicing factors. Dysregulation of tau exon 10 pre-mRNA splicing causes pathological imbalances in 3R- and 4R-tau, leading to neurodegeneration; however, the role of SRPK2 in these processes remains unclear. Here we show that delta-secretase (also known as asparagine endopeptidase; AEP), which is activated in AD, cleaves SRPK2 and in ...[more]

PMID: 30373880

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Project description:ObjectiveThe goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories.MethodsParticipants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18 F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aβ-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline.ResultsWomen showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). β-amyloid (Aβ)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aβ + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04).InterpretationTau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aβ were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932.

Dataset Information

Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies.

Publications

Delta-secretase (AEP) mediates tau-splicing imbalance and accelerates cognitive decline in tauopathies.

Similar Datasets

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