Biology subjects

Papageorgopoulou, M.

Publications and source records attributed to Papageorgopoulou, M..

4 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

Stage-specific proteomic signatures of synaptopathy in Alzheimers disease

Synapse loss is the strongest pathological correlate of cognitive decline in Alzheimers disease, yet the molecular basis of synaptic vulnerability across disease progression remains poorly understood. We performed proteomic profiling of isolated synaptoneurosomes from post-mortem middle temporal gyrus tissue from 67 individuals, comprising 40 individuals spanning all Alzheimers disease Braak stages and 27 non-diseased controls. Differential abundance and weighted gene co-expression network analyses were combined with pathway, cell-type and gene set variation analyses to characterise stage-associated changes in the synaptic proteome. Brain-derived candidate proteins were subsequently evaluated using receiver operating characteristic and regression analyses against cognitive examination scores in two independent plasma proteomics datasets. We identified six distinct stage-associated synaptic proteomic signatures. Mitochondrial function and synaptic signalling declined by mid-stage Alzheimers disease, while clathrin-mediated endocytosis increased at mid-stage without further change at later stages. By contrast, proteostasis and perisynaptic astrocytic processes increased progressively throughout the disease course. Global excitatory and inhibitory protein signals also showed a progressive shift in their relative balance (P = 7.80 x 10-3; adjusted R{superscript 2} = 0.072). These findings guided targeted investigation of candidate plasma markers linked to distinct synaptic processes in two independent proteomic datasets. We nominated 42 plasma proteins mapping to synaptic signatures of progression, which showed associations with disease stage and cognitive measures including Mini-Mental State Examination, Montreal Cognitive Assessment and Clinical Dementia Rating. PHGDH was prioritised across analyses through associations with cognitive impairment from early disease stages (Clinical Dementia Rating transition 0 to 0.5, false discovery rate = 8.87 x 10-18), neuropathological progression (P = 6.85 x 10-7) and excitatory-inhibitory protein imbalance (P = 5.56 x 10-3). Together, our findings define the stage-associated molecular changes at the AD synapse and connect distinct brain pathways to accessible plasma candidates, establishing a mechanistically anchored framework for future patient stratification and evaluation of synapse-directed therapies.

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↗

bioRxiv2026

ABCA7 rs3752231 variant effects on glial responses to amyloid-β and plaque maturation in Alzheimer's disease.

Variants in ABCA7 are among the most consistently replicated genetic risk factors for late-onset Alzheimers disease (AD), yet the cellular mechanisms remain poorly defined. Here, we characterise the impact of the common ABCA7 rs3752231 risk variant on amyloid-{beta} (A{beta}) pathology and glial responses in human post-mortem brain, combining quantitative neuropathology of 4G8-immunostained mid-temporal gyrus from 99 donors (Braak 0-VI) with glial-enriched single-nucleus RNA sequencing from 54 of them. ABCA7 rs3752231 carriers exhibited an increased A{beta} burden and larger plaques with late AD explained by a selective expansion of diffuse plaques and relative reduction in compact plaques, consistent with impaired microglial-mediated plaque maturation. Transcriptional responses to increasing A{beta} burden were largely genotype-specific: non-carriers showed canonical disease-associated microglial activation, including upregulation of complement, phagocytic, and inflammatory pathways, alongside astrocyte responses consistent with preserved synaptic support, while carriers exhibited a distinguishable activation state. Exploratory ligand-receptor analysis identified carrier-specific intercellular signals suggesting non-cell autonomous suppression of microglial phagocytosis. Together, these findings position ABCA7 rs3752231 as a regulator of glial responses to AD pathology, linking a common coding variant to impaired microglial plaque containment and maladaptive astrocyte responses and nominate microglial TREM2 activation and CD33 inhibition and astrocytic EAAT2 induction as candidate therapeutic strategies.

neuroscience↗