Flanagan, M. E. | bioRxiv Science

bioRxiv2021

Genome-wide association study and functional validation implicates JADE1 in tauopathy

Primary age-related tauopathy (PART) is a neurodegenerative tauopathy with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-{beta} (A{beta}) deposition in plaques. The pathogenesis of PART is unknown, but evidence suggests it is associated with genes that promote tau pathology as well as others that protect from A{beta} toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n=647) using Braak neurofibrillary tangle stage as a quantitative trait adjusting for sex, age, genotyping platform, and principal components. We found significant associations with some candidate loci associated with AD and progressive supranuclear palsy, a primary tauopathy (SLC24A4, MS4A6A, HS3ST1, MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brain from tauopathies containing isoforms with four microtubule-binding domain repeats (4R) and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation revealed a direct and specific binding of JADE1 protein to tau containing four (4R) and no N-terminal inserts (0N4R) in post-mortem human PART brain tissue. Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a mediator of neurofibrillary degeneration.

neuroscience↗

bioRxiv2021

Deep learning from multiple experts improves identification of amyloid neuropathologies

Pathologists can label pathologies differently, making it challenging to yield consistent assessments in the absence of one ground truth. To address this problem, we present a DL approach that draws on a cohort of experts, weighs each contribution, and is robust to noisy labels. We collected 100,495 annotations on 20,099 candidate amyloid beta neuropathologies (cerebral amyloid angiopathy (CAA), and cored and diffuse plaques) from three institutions, independently annotated by five experts. DL methods trained on a consensus-of-two strategy yielded 12.6-26% improvements by area under the precision recall curve (AUPRC) when compared to those that learned individualized annotations. This strategy surpassed individual-expert models, even when unfairly assessed on benchmarks favoring them. Moreover, ensembling over individual models was robust to hidden random annotators. In blind prospective tests of 52,555 subsequent expert-annotated images, the models labeled pathologies like their human counterparts (consensus model AUPRC=0.74 cored; 0.69 CAA). This study demonstrates a means to combine multiple ground truths into a common-ground DL model that yields consistent diagnoses informed by multiple and potentially variable expert opinion.

pathology↗