Biology subjects

Fancy, N. N.

Publications and source records attributed to Fancy, N. N..

3 recordsLinked to original sources

bioRxiv2026

Neuronal and glial transcriptional states vary with proximity to tangle-bearing neurons in the human entorhinal cortex

More neurons die in Alzheimer's disease than form tangles, and tangle-bearing neurons can persist for decades, so tangles alone cannot explain degeneration. We combined 6,000-plex spatial transcriptomics with PHF1 immunofluorescence (167,176 cells; 9 donors) and imaging mass cytometry (170,195 cells; 62 donors), measuring each cell's distance to the nearest tangle. Tangle-bearing layer 2-3 excitatory neurons were enriched late along a trajectory of increasing microtubule-associated, synaptic and V-ATPase expression, with elevated p62 and K48-ubiquitin. Tangle-free neurons shared more of this state the closer they lay to a tangle, including higher chaperone and autophagy scores, p62 and nuclear size. Nearby glia had higher disease-associated scores, with astrocytes expressing less GFAP. Excitatory, but not inhibitory, neuron loss was greatest in subtypes closest to tangles and cortical depths richest in phosphorylated tau. Selective neuronal vulnerability may reflect not only a neuron's susceptibility to forming a tangle but also where it lies relative to one.

neuroscience↗

bioRxiv2026

Intrinsic molecular susceptibility underlies selective neuronal vulnerability in the Alzheimer's disease entorhinal cortex

Entorhinal cortex (EC) excitatory neurons are lost early in Alzheimers disease (AD), yet the specific subtype and characteristics contributing to this vulnerability are poorly understood. Combining imaging mass cytometry (206,913 cells; 62 donors) and single nucleus RNA sequencing (42,780 nuclei; 36 donors) of post-mortem EC, we found that calbindin-expressing layer 2-3 excitatory neurons accumulate high phospho-tau burden and are preferentially lost in AD. In non-diseased brains, these neurons exhibit elevated tau-modifying kinase expression (ERK1/2, FYN, ROCK), reduced phosphatase expression (PP2A/B, PP5) and low mitochondrial respiratory capacity which together are predicted to promote high vulnerability to tau pathology. Trajectory analysis resolved progression from homeostasis through DNA damage and proteostatic stress to developmental re-entry and death priming. In silico screening suggested histone deacetylase inhibitors and cyclooxygenase inhibitors as candidate resilience-promoting therapeutics. Our work thus reframes intrinsic features of neuronal identity promoting phospho-tau formation as modifiable determinants of the selective vulnerability of EC calbindin neurons.

neuroscience↗

bioRxiv2021

Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology

To better define roles that astrocytes and microglia play in Alzheimers disease (AD), we used single-nuclei RNA sequencing to comprehensively characterize transcriptomes in astrocyte and microglia nuclei isolated post mortem from neuropathologically-defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid and pTau expression. Astrocytes were enriched for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, proteostasis and autophagy were highly enriched in microglia and perivascular macrophages. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.

neuroscience↗