Biology subjects

Caramello, A.

Publications and source records attributed to Caramello, A..

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↗

bioRxiv2020

Dentate gyrus development requires a cortical hem-derived astrocytic scaffold.

During embryonic development, radial glial cells give rise to neurons, then to astrocytes following the gliogenic switch. Timely regulation of the switch, operated by several transcription factors, is fundamental for allowing coordinated interactions between neurons and glia. We deleted the gene for one such factor, SOX9, early during mouse brain development and observed a significantly compromised dentate gyrus (DG). We dissected the origin of the defect, targeting embryonic Sox9 deletion to either the DG neuronal progenitor domain or the adjacent cortical hem (CH). We identified in the latter previously uncharacterized ALDH1L1+ astrocytic progenitors, which form a fimbrial-specific glial scaffold necessary for neuronal progenitor migration towards the developing DG. Our results highlight an early crucial role of SOX9 for DG development through regulation of astroglial potential acquisition in the CH. Moreover, we illustrate how formation of a local network, amidst astrocytic and neuronal progenitors originating from adjacent domains, underlays brain morphogenesis.

developmental biology↗