Dataset Information

Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome

ABSTRACT: Down syndrome (DS) is the most prevalent genetic abnormality, occurring in ~1/700 live births caused by triplication of human chromosome 21 (HSA21). DS individuals have a multitude of phenotypic changes in peripheral systems and most notably, are cognitively impaired, with deficits in learning, language and memory acquisition and consolidation. Further, individuals with DS develop Alzheimer’s disease (AD) pathology during early middle-age (mid-30’s), although the underlying mechanism(s) driving this pathology onset are not well understood. Contributing to cognitive impairment in DS, morphological deficits are present in cortical lamination and distribution, with Layer III (L3) and Layer V (L5) pyramidal neurons showing reduced proliferation and a disorganized laminar structure. As such, examining cortical L3 and L5 pyramidal neurons in DS individuals with AD pathology may elucidate alternate driver mechanisms of disease onset. We examined DS and age-matched control (CTR) brains from individuals without intellectual disabilities or dementia using postmortem frontal cortex (BA9) via single population low input RNA-sequencing. We specifically targeted L3 and L5 pyramidal neurons to understand circuitry-based alterations in DS/AD individuals to elucidate mechanistic drivers of disease pathology. We show convergent and divergent gene expression changes in L3 and L5 pyramidal neurons which may underlie cognitive deficits and degenerative pathology associated with aging in the DS brain. We pinpoint alterations in HSA21 gene expression as well as a multitude of convergent differentially expressed genes (DEGs) and relevant pathways via bioinformatic inquiry in the DS brains that underlie mechanisms of degeneration. Distinctly, convergent gene expression reveals a neurotoxic phenotype, with multiple canonical pathways of dysregulation and disease functions linked to the convergent DEGs, including downregulation of the CLEAR signaling pathway and significantly increased activation of the neuroinflammation signaling pathway. We identify several target genes including mitogen activated protein kinase 1 and 3 (MAPK1/3), calcium voltage-gated channel subunit alpha1 A (CACNA1A) and superoxide dismutase 1 (SOD1), which exhibit overlap in multiple pathways and disease functions and/or display dysfunctional protein-protein network interactions for further examination. Novel targets identified by our single population approach in L3 and L5 pyramidal neurons may be drivers of the disease mechanism and therefore may be therapeutic candidates for amelioration of degenerative pathology that targets memory and executive function circuits in DS/AD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE251939 | GEO | 2024/08/07

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Dataset Information

Analysis of microisolated frontal cortex excitatory layer III and V pyramidal neurons reveals a neurodegenerative phenotype in individuals with Down syndrome

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets