Lundby, J. M. B. | bioRxiv Science

bioRxiv2026

STAT1 sets microglial neutral-lipid content independently of lipid-handling transcriptional programs

Inflammatory activation and lipid remodeling are linked features of microglial states, but how inflammatory transcription factors shape microglial lipid handling is unclear. Here we show that STAT1 sets neutral-lipid content in microglia through a route not predicted by lipid-handling transcription. Acute STAT1 depletion in primary microglia lowered neutral-lipid content while lipid-uptake and lipid-storage programs were induced, and interferon-{gamma} activation moved inflammatory transcription in the opposite direction yet lowered lipid content alike. Single-cell transcriptomic and chromatin profiling of Stat1- and Irf1-deficient mice showed that STAT1 and IRF1 organize overlapping inflammatory and lipid-handling programs, with genome-wide accessibility changes that did not predict transcriptional output at individual lipid-handling loci. Microglia co-expressing STAT1 and APOE recurred across Alzheimer's disease and multiple sclerosis datasets. Transcriptional program engagement is therefore separable from cellular lipid state, and lipid-handling gene expression cannot be read as a proxy for microglial lipid content.

neuroscience↗

bioRxiv2026

Population-specific transcriptional-state remodeling of cortical and hypothalamic neurons in Alzheimer's disease

Selective neuronal vulnerability shapes Alzheimer's disease, but it is commonly inferred from changes in the relative representation of neuronal populations rather than from molecular changes within those populations. We mapped both dimensions across disease progression in amyloid, tau, and combined amyloid-tau mouse models, extended the analysis to cortex and hypothalamus in an independent tau model, and tested the resulting framework in human Alzheimer's disease. Populations with similar reductions in representation showed markedly different degrees of molecular remodeling, while substantial state changes also occurred in populations whose representation remained close to wild type. Disease altered excitability, synaptic, and regulatory programs and reshaped the distribution of cellular states within matched neuronal identities. A particularly recurrent excitatory state linked CAMKK2-AMPK signaling with microtubule regulation. It expanded in glutamatergic populations early in the combined amyloid-tau model, but its direction was not fixed: the same state reversed with age in dentate granule-like neurons and was reduced in corticothalamic neurons of an independent tau model. Remodeling extended beyond cortex to hypothalamic Hdc-positive tuberomammillary neurons, which showed focused excitability-associated changes despite representation close to wild type. In human Alzheimer's disease, remodeling was strongest in several deep-layer and RORB-positive excitatory populations independently associated with vulnerability. The CAMKK2-AMPK-associated state was predominantly reduced rather than increased. An independently defined human depletion-associated neuronal identity instead overlapped other synaptic and calcium-signaling components of the same broader remodeling architecture. Neuronal involvement in Alzheimer's disease is therefore expressed as structured, population-specific remodeling of molecular state, extending across cortical and hypothalamic identities and only partly reflected in relative representation.

neuroscience↗