Conserved cell-type specific signature of resilience to Alzheimer’s disease nominates role for excitatory intratelencephalic cortical neurons
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PROVIDER: PRJNA915395 | ENA |
REPOSITORIES: ENA
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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.
2023-12-23 | GSE221702 | GEO
Project description:The cerebral cortex is a cellularly-complex structure comprised of a rich diversity of neuronal and glial cell types. Cortical neurons can be broadly categorized into two classes—glutamatergic excitatory neurons and GABAergic inhibitory interneurons. Previous developmental studies in rodents have led to the prevailing model that while excitatory neurons are born from progenitors located in the cortex, cortical interneurons are born from a separate population of progenitors located outside of the developing cortex in the ganglionic eminences1-5. However, the developmental potential of human cortical progenitors has not been thoroughly explored. Here we show that in addition to excitatory neurons and glia, human cortical progenitors are also capable of producing GABAergic neurons with the transcriptional characteristics and morphologies of cortical interneurons. By developing a cellular barcoding tool called “ScRNAseq-compatible Tracer for Identifying Clonal Relationships” (STICR), we were able to perform clonal lineage tracing of 1912 primary human cortical progenitors from six specimens and capture both the transcriptional identities and clonal relationships of their resulting progeny. A subpopulation of cortically-born GABAergic neurons were transcriptionally similar to cortical interneurons born from the caudal ganglionic eminence and these cells were frequently related to excitatory neurons and glia. Thus, our results demonstrate that individual human cortical progenitors can generate both excitatory neurons and cortical interneurons, providing a new framework for understanding the origins of neuronal diversity in the human cortex.
2021-11-06 | GSE187875 | GEO
Project description:Single-cell omics is advancing our understanding of selective neuronal vulnerability in Alzheimer’s disease (AD), revealing specific subtypes that are either susceptible or resilient to neurodegeneration. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex and precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing RORB, CUX2, and EYA4. Layer 4 neurons in association neocortex shared overlapping molecular signatures of resilience. Early in the disease, resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotective factors, including GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1, and CSMD1. We also identified KCNIP4, which encodes a voltage-gated potassium (Kv) channel-interacting protein that interacts with Kv4.2 channels and presenilins, as a key factor linked to resilience. KCNIP4 was consistently upregulated in the early stages of pathology. Furthermore, AAV-mediated overexpression of Kcnip4 in a humanized AD mouse model reduced the expression of the activity-dependent genes Arc and c-Fos, suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a valuable resource for investigating mechanisms underlying resilience to neurodegeneration.
2025-08-24 | GSE263468 | GEO
Project description:Alzheimer’s Disease is a devastating and an irreversible neurodegenerative disease currently afflicting 50 million individuals worldwide, a number expected to escalate three-fold over the next 25 years. Preventative treatment is of dire importance, and yet, cellular mechanisms underlying early regional vulnerability in Alzheimer’s Disease remain unknown. In human patients with Alzheimer’s Disease, the earliest observed pathophysiological correlate to cognitive decline is hyperexcitability. In mouse models, early hyperexcitability has been shown in the cortical region first impacted by Alzheimer’s Disease. The origin of hyperexcitability in early stage-disease and why it preferentially emerges in specific regions is unclear. Using cortical-region and cell-type- specific proteomics and patch-clamp electrophysiology, we uncovered differential susceptibility to human-specific APP in a model of sporadic Alzheimer’s Disease. Shockingly, our findings reveal that early entorhinal hyperexcitability may result from intrinsic vulnerability of parvalbumin interneurons, prior to changes in surrounding excitatory neurons. This study suggests early disease interventions addressing non-excitatory cell-types may protect regions first vulnerable to pathological symptoms of Alzheimer’s Disease and downstream cognitive decline.
2024-06-28 | PXD053491 | Pride
Project description:MYT1L deficiency impairs excitatory neuron trajectory during cortical development
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Project description:CHD8 mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. Chd8+/- mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nuclei transcriptomics (snRNA-seq), we found increased Chd8+/- cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive Chd8+/- and conditional Camk2a-Cre Chd8+/- mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found Chd8+/- mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, Chd8 haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.
2026-01-01 | GSE301511 | GEO
Project description:CHD8 mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. Chd8+/- mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nuclei transcriptomics (snRNA-seq), we found increased Chd8+/- cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive Chd8+/- and conditional Camk2a-Cre Chd8+/- mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found Chd8+/- mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, Chd8 haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.
2026-01-01 | GSE300997 | GEO
Project description:Numerous genetic variants associated with MEF2C are linked to autism, intellectual disability (ID) and schizophrenia (SCZ) – a heterogeneous collection of neurodevelopmental disorders with unclear pathophysiology. MEF2C is highly expressed in developing cortical excitatory neurons, but its role in their development remains unclear. We show here that conditional embryonic deletion of Mef2c in cortical and hippocampal excitatory neurons (Emx1-lineage) produces a dramatic reduction in cortical network activity in vivo, due in part to a dramatic increase in inhibitory and a decrease in excitatory synaptic transmission. In addition, we find that MEF2C regulates E/I synapse density predominantly as a cell-autonomous, transcriptional repressor. Analysis of differential gene expression in Mef2c mutant cortex identified a significant overlap with numerous synapse- and autism-linked genes, and the Mef2c mutant mice displayed numerous behaviors reminiscent of autism, ID and SCZ, suggesting that perturbing MEF2C function in neocortex can produce autistic- and ID-like behaviors in mice.
2016-09-23 | GSE87202 | GEO
Project description:MYT1L deficiency impairs excitatory neuron trajectory during cortical development [E14]
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Project description:MYT1L deficiency impairs excitatory neuron trajectory during cortical development [P1]
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