Pathological Validation of RORB and CDH9 as Selectively Vulnerable Neurons in Alzheimer's Disease. (20th December 2022)

• Record Type: Journal Article
• Authors: Nasar, Rakin T; Pereira, Felipe Luiz; Li, Song Hua; Miramontes, Silvia; Kampmann, Martin; Leng, Kun; Seeley, William W.; Spina, Salvatore; Miller, Bruce L.; Grinberg, Lea Tenenholz
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.062034
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: : The excitatory neurons of the entorhinal cortex are extremely vulnerable to Alzheimer's disease (AD). Recently, we demonstrated that among those neurons, expressing high levels of RORB, are more vulnerable than other neighboring excitatory neuronal subpopulations. Our single nucleus RNA sequencing of 10 EC at progressive stages of AD neurofibrillary pathology also suggested that CDH9+ excitatory neurons from the EC can also be early vulnerable to AD. Here, we used quantitative neuropathological methods in cases across AD progression to interrogate whether CDH9+ neurons are early vulnerable to AD. Method: We used quantitative histopathological assessment using multiplex immunofluorescence to quantify the number of NeuN+, T231+, CDH9+, and RORB+ cells in 18 cases across Braak stages 0‐V1. All cases were 8μm thick, formalin‐fixed and paraffin embedded coronal sections of EC. Slides stained with hematoxylin and eosin were used to delineate the EC boundaries and identifying clusters of stellate cells in layer II. Neuronal quantification of EC external layers was done using an in‐house automated cell counting tool with manual quality control and using the ImageJ cell counter plugin. Result: The number of neurons (NeuN+) decreased along the Braak stages II‐VI (p<0.01) (Fig. 1A), whereas the proportion of ptau+ (T231) neurons increased stages II‐VI (p<0.001) (Fig. 1B). CDH9+ neurons had a significantly higher proportion of T231 colocalization in Braak stages II‐IV (p<0.01) and IV‐VI (p<0.05) compared to 0‐II (Fig. 1G). We observed a trend on neuronal loss, but it did not reach statistical significance (Fig. 1C, E). Similar results were observed to the RORB+ neuronal population (Fig. 1 D, F H). Conclusion: CDH9+ and RORB+ cells are more likely to accumulate tau compared to non‐CDH9+ and non‐RORB+ cells. RORB+ and CDH+ cells are more likely to accumulate tau in Braak stages II‐IV, but the relationship is not linear, and the accumulation plateaus in the Braak stages IV‐VI. The trend of CDH9+ and RORB+ cell loss did not reach statistical significance, suggesting this pilot study is still underpowered. The results confirm that CDH9+ and RORB+ cells are selectively vulnerable to tau pathology.