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. 2023 Aug 21;18(1):57.
doi: 10.1186/s13024-023-00646-z.

TDP-43-regulated cryptic RNAs accumulate in Alzheimer's disease brains

Virginia Estades Ayuso  1   2 , Sarah Pickles  1   2 , Tiffany Todd  1   2 , Mei Yue  1 , Karen Jansen-West  1 , Yuping Song  1 , Jesús González Bejarano  1 , Bailey Rawlinson  1 , Michael DeTure  1   2 , Neill R Graff-Radford  3 , Bradley F Boeve  4 , David S Knopman  4 , Ronald C Petersen  4 , Dennis W Dickson  1   2 , Keith A Josephs  4 , Leonard Petrucelli  1   2 , Mercedes Prudencio  5   6   7
Affiliations

TDP-43-regulated cryptic RNAs accumulate in Alzheimer's disease brains

Virginia Estades Ayuso et al. Mol Neurodegener. .

Abstract

Background: Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer's disease (AD). Approximately, 30-70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis.

Methods: To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively.

Results: We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls.

Conclusions: Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.

Keywords: Alzheimer’s disease; Cryptic RNA; LATE; STMN2; TDP-43.

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Conflict of interest statement

BFB receives institutional research grant support from Alector, Biogen, Transposon, Cognition Therapeutics, and GE Healthcare. BFB receives honorarium for SAB activities for the Tau Consortium. LP is a consultant for Expansion Therapeutics. DSK serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study. DSK served on a Data Safety monitoring Board for a tau therapeutic for Biogen (until 2021) but received no personal compensation. DSK is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. DSK has served as a consultant for Roche, Samus Therapeutics, Magellan Health, Biovie and Alzeca Biosciences but receives no personal compensation. DSK attended an Eisai advisory board meeting for lecanemab on December 2, 2022, but received no compensation. DSK receives funding from the NIH. All other authors declare no disclosures or conflicts of interest related to the content of the article.

Figures

Fig. 1
Fig. 1
TDP-43 pathology accumulates in amygdala and hippocampus of AD-TDP. (A) Graphical overview of AD-TDP staging based on TDP-43 deposition pattern from amygdala (stage 1), followed by the hippocampus and occipitotemporal gyrus (stages 2–3), basal forebrain and ventral striatum (stages 4–5) and last in the frontal cortex (stage 6). Created with BioRender.com. (B) Quantification of pTDP-43 protein levels in cognitively normal controls (CN), AD and FTLD cohorts across three brain regions: amygdala, hippocampus, and frontal cortex (see Table 1), using an immunoassay (see Methods). Data are presented as mean ± SEM. Number of cases is included in the figures. Statistical analyses were performed by One-way ANOVA following Dunn’s multiple comparison tests: *P < 0.05, **P < 0.005, *** P < 0.0005, ****P < 0.0001, ns: not significant
Fig. 2
Fig. 2
Aberrant cryptic RNAs accumulate in the amygdala and hippocampus of AD-TDP. Cryptic RNA (STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7) levels were measured by qRT-PCR in amygdala (A) and hippocampus (B) of controls (Ctrl: CN, represented by white circles + AD no TDP, represented by orange circles), AD-TDP, and FTLD-TDP cases. Number of cases is included in the figures. Data are presented as mean ± SEM. Statistical analyses were performed by One-way ANOVA following Dunn’s multiple comparison tests: *P < 0.05, **P < 0.005, *** P < 0.0005, ****P < 0.0001, ns: not significant
Fig. 3
Fig. 3
Cryptic RNA can discriminate AD-TDP cases from controls. (A) Representative images of the discriminatory ability of cryptic RNAs to distinguish AD-TDP cases from controls, evaluated by receiver operating characteristic (ROC) analyses, in amygdala (left; AD-TDP, N = 69; controls, N = 49) and hippocampus (right; AD-TDP, N = 71; controls, N = 54). The area under the curve (AUC) values, 95% confidence intervals (CI), and P values for each cryptic RNA are included in the bottom table. (B) Representative image of the comparable discriminatory ability pattern of cryptic RNAs for AD-TDP and FTLD-TDP cases in the amygdala
See this image and copyright information in PMC

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