Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder, the molecular and cellular complexity of which remains poorly understood. Here, we profiled and analysed 80,660 single-nucleus transcriptomes from prefrontal cortex of 48 individuals with varying degrees of AD pathology. We identified transcriptionally-distinct subpopulations across six major brain cell-types, including those associated with pathology and characterized by regulators of myelination, inflammation, and neuron survival. The strongest AD-associated changes appeared early in pathological progression and were highly cell-type-specific, whereas genes upregulated in late-stage were common across cell types and primarily involved in global stress response. Surprisingly, we found an overrepresentation of female cells in AD-associated subpopulations, and substantially different transcriptional responses between sexes in multiple cell types, including oligodendrocytes. Overall, myelination-related processes were recurrently perturbed in multiple cell types, suggesting a key role in AD pathophysiology. Our single-cell transcriptomic resource provides a first blueprint for interrogating the molecular underpinnings and cellular basis of AD.

Changes in gamma oscillations (20-50 Hz) have been observed in several neurological disorders. However, the relationship between gamma and cellular pathologies is unclear. Here, we show reduced behaviorally-driven gamma before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer's disease (AD). Optogenetically driving FS-PV-interneurons at gamma (40 Hz), but not other frequencies, reduced levels of amyloid-β (A β)1-40 and A β1-42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia and histological analysis confirmed increased microglia co-localization with A β. Subsequently, we designed a non-invasive 40 Hz light-flickering paradigm that reduced A β1-40 and A β1-42 levels in visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate AD-associated pathology.

SUMMARY Neuronal activity causes the rapid expression of immediate early genes that are crucial for experience-driven changes to synapses, learning, and memory. Here, using both molecular and genome-wide next-generation sequencing methods, we report that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1. Generation of targeted DNA DSBs within Fos and Npas4 promoters is sufficient to induce their expression even in the absence of an external stimulus. Activity-dependent DSB formation is likely mediated by the type II topoisomerase, Topoisomerase IIβ (Topo IIβ), and knockdown of Topo IIβ attenuates both DSB formation and early-response gene expression following neuronal stimulation. Our results suggest that DSB formation is a physiological event that rapidly resolves topological constraints to early-response gene expression in neurons.