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A Scalable Human Brain Cell Atlas Dissects the Microglial Immune Codes and Cognitive Resilience

ABSTRACT: The biological basis of resilience to cognitive decline and Alzheimer’s disease (AD) remains unclear, hindering the development of effective interventions for brain health. Here, we present the largest human brain single-nucleus RNA-seq atlas to date (~14 million nuclei across 31 brain regions from 2,239 deeply phenotyped postmortem samples, including cognitively normal (CN), AD (clinico-pathologically confirmed), cognitively resilient (CR), and primary age-related tauopathy (PART)), using a scalable generative artificial intelligence framework. This resource identifies >50 neuronal and glial cell types and reveals a linkage of mitochondrial bioenergetics in somatostatin (SST) neurons to cognitive resilience in the presence of amyloid-beta and tau pathology, which we validated immunohistochemically. We also identified that the microglia-associated genes PLCG2 and GPNMB were associated with AD progression in an age-independent manner. Genes encoding interferon signaling pathways (e.g., IFIT3 and IFI44) were identified as female-specific markers in disease-associated microglia. We also identified glutamate signaling-mediated immune-neuron crosstalks associated with AD etiologies, which was experimentally validated by transcriptomic signatures in patient iPSC-derived microglia. In summary, this comprehensive brain cell atlas deciphers brain-immune interactions underlying brain resilience and offers an open-access platform to accelerate therapeutic development for AD and brain health if broadly applied.

ORGANISM(S): Homo sapiens

PROVIDER: GSE326002 | GEO | 2026/09/22

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease-modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. In this study, we use single-nucleus transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid load. Our cross-species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GRIA3, KCNMA1, and STXBP1. This putative cell type has been implicated in resilience in previous studies on bulk RNA-seq tissue, but our single-nucleus and cross-species approach identifies particular resilience-associated gene signatures in these cells. These novel resilience candidate genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Based on these gene signatures, we identified several potential mechanisms of resilience, including regulation of synaptic plasticity, axonal and dendritic development, and neurite vesicle transport along microtubules that are potentially targetable by available therapeutics. Because our discovery of resilience-associated genes in layer 4/5 cortical neurons originates from an integrated human and mouse transcriptomic space from susceptible and resilient individuals, we are positioned to test causality and perform mechanistic, validation, and pre-clinical studies in our human-relevant AD-BXD mouse panel.

Project description:Microglia and neuroinflammation are implicated in the development and progression of Alzheimer’s disease (AD). To better understand microglia-mediated processes in AD, we studied the function of INPP5D/SHIP1, a gene linked to AD through GWAS. Immunostaining and single nucleus RNA sequencing confirmed that INPP5D expression in the adult human brain is enriched in microglia. Examination of prefrontal cortex across a large cohort revealed reduced full-length soluble INPP5D protein levels in AD patient brains compared to cognitively normal controls. However, elevated INPP5D immunostaining in microglia in the AD brain was observed, which was driven by elevations in plaque-associated microglia suggesting that these two methods quantify different pools of INPP5D. Examination of INPP5D overexpression and bi-allelic loss-of-function in induced pluripotent stem cell derived microglia (iMGs) revealed that INPP5D LOF most closely resemble microglia in the AD brain with respect to immune signaling alterations, supporting the hypothesis that INPP5D function is reduced in AD microglia. The functional consequences of reduced INPP5D activity were evaluated in human iMGs, using both pharmacological inhibition of the phosphatase activity of INPP5D and genetic reduction in copy number. Unbiased transcriptional and proteomic profiling of these iMGs suggested an upregulation of innate immune signaling pathways, lower levels of scavenger receptors, reduced lysosomal proteins and altered inflammasome signaling with INPP5D reduction. INPP5D inhibition induced the secretion of IL-1ß and IL-18, further implicating inflammasome activation. Inflammasome activation was confirmed through visualization of inflammasome formation through ASC immunostaining in INPP5D-inhibited iMGs, increased cleaved caspase-1 and through rescue of elevated IL-1ß and IL-18 with caspase-1 and NLRP3 inhibitors. In accord, lower INPP5D is associated with higher IL-18 levels and an elevation in microglia with ASC specks in the AD brain. This work implicates INPP5D as a regulator of inflammasome signaling in human microglia.

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A Scalable Human Brain Cell Atlas Dissects the Microglial Immune Codes and Cognitive Resilience

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