Biology subjects

Martini, A. C.

Publications and source records attributed to Martini, A. C..

3 recordsLinked to original sources

bioRxiv2023

Learning fast and fine-grained detection of amyloid neuropathologies from coarse-grained expert labels

Precise, scalable, and quantitative evaluation of whole slide images is crucial in neuropathology. We release a deep learning model for rapid object detection and precise information on the identification, locality, and counts of cored plaques and cerebral amyloid angiopathies (CAAs). We trained this object detector using a repurposed image-tile dataset without any human-drawn bounding boxes. We evaluated the detector on a new manually-annotated dataset of whole slide images (WSIs) from three institutions, four staining procedures, and four human experts. The detector matched the cohort of neuropathology experts, achieving 0.64 (model) vs. 0.64 (cohort) average precision (AP) for cored plaques and 0.75 vs. 0.51 AP for CAAs at a 0.5 IOU threshold. It provided count and locality predictions that correlated with gold-standard CERAD-like WSI scoring (p=0.07{+/-} 0.10). The openly-available model can quickly score WSIs in minutes without a GPU on a standard workstation.

pathology↗

bioRxiv2021

Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimers Disease

Microglia are critical for brain development and play a central role in Alzheimers disease (AD) etiology. Down syndrome (DS), also known as trisomy 21, is the most common genetic origin of intellectual disability and the most common risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglia in DS brain development and AD in DS (DSAD). Using our new induced pluripotent stem cell (iPSC)-based human microglia-containing cerebral organoid and chimeric mouse brain models, here we report that DS microglia exhibit enhanced synaptic pruning function during brain development. Consequently, electrophysiological recordings demonstrate that DS microglial mouse chimeras show impaired synaptic functions, as compared to control microglial chimeras. Upon being exposed to human brain tissue-derived soluble pathological tau, DS microglia display dystrophic phenotypes in chimeric mouse brains, recapitulating microglial responses seen in human AD and DSAD brain tissues. Further flow cytometry, single-cell RNA- sequencing, and immunohistological analyses of chimeric mouse brains demonstrate that DS microglia undergo cellular senescence and exhibit elevated type I interferon signaling after being challenged by pathological tau. Mechanistically, we find that shRNA-mediated knockdown of Hsa21encoded type I interferon receptor genes, IFNARs, rescues the defective DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide first in vivo evidence supporting a paradigm shifting theory that human microglia respond to pathological tau by exhibiting accelerated senescence and dystrophic phenotypes. Our results further suggest that targeting IFNARs may improve microglial functions during DS brain development and prevent human microglial senescence in DS individuals with AD.

neuroscience↗

bioRxiv2021

Transcriptomic similarities and differences between mouse models and human Alzheimer's Disease

Alzheimers disease (AD) is a multifactorial pathology, with most cases having a sporadic origin. Recently, knock-in (KI) models have been developed with the promise of resembling better sporadic human AD, such as the novel hA{beta}-KI mouse. Here, we compared hippocampal publicly available transcriptomic profiles of transgenic (5xFAD and APP/PS1) and KI (hA{beta}-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. Experimental validation of consistently dysregulated genes revealed four altered in mice (SLC11A1, S100A6, CD14, CD33, C1QB) and three in humans (S100A6, SLC11A1, KCNK). Additionally, the three mouse models presented more Gene Ontology biological processes terms and enriched signaling pathways in common with LOAD than with EOAD individuals. Finally, we identified 17 transcription factors potentially acting as master regulators of AD. Our cross-species analyses revealed that the three mouse models presented a remarkable similarity to LOAD, with the hA{beta}-KI being the more specific one.

neuroscience↗