Dataset Information

Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability.

ABSTRACT: Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. A?, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from A? plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable) and caudal fates (relatively spared) in AD. We find that both the generation of A? and the responsiveness of TAU to A? are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD.

SUBMITTER: Muratore CR

PROVIDER: S-EPMC5785690 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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Publications

Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability.

Muratore Christina R CR Zhou Constance C Liao Meichen M Fernandez Marty A MA Taylor Walter M WM Lagomarsino Valentina N VN Pearse Richard V RV Rice Heather C HC Negri Joseph M JM He Amy A Srikanth Priya P Callahan Dana G DG Shin Taehwan T Zhou Monica M Bennett David A DA Noggle Scott S Love J Christopher JC Selkoe Dennis J DJ Young-Pearse Tracy L TL

Stem cell reports 20171116 6

Alzheimer's disease (AD) induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aβ, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aβ plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients h ...[more]

PMID: 29153990

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Project description:Brain connectivity studies have revealed that highly connected 'hub' regions are particularly vulnerable to Alzheimer pathology: they show marked amyloid-β deposition at an early stage. Recently, excessive local neuronal activity has been shown to increase amyloid deposition. In this study we use a computational model to test the hypothesis that hub regions possess the highest level of activity and that hub vulnerability in Alzheimer's disease is due to this feature. Cortical brain regions were modeled as neural masses, each describing the average activity (spike density and spectral power) of a large number of interconnected excitatory and inhibitory neurons. The large-scale network consisted of 78 neural masses, connected according to a human DTI-based cortical topology. Spike density and spectral power were positively correlated with structural and functional node degrees, confirming the high activity of hub regions, also offering a possible explanation for high resting state Default Mode Network activity. 'Activity dependent degeneration' (ADD) was simulated by lowering synaptic strength as a function of the spike density of the main excitatory neurons, and compared to random degeneration. Resulting structural and functional network changes were assessed with graph theoretical analysis. Effects of ADD included oscillatory slowing, loss of spectral power and long-range synchronization, hub vulnerability, and disrupted functional network topology. Observed transient increases in spike density and functional connectivity match reports in Mild Cognitive Impairment (MCI) patients, and may not be compensatory but pathological. In conclusion, the assumption of excessive neuronal activity leading to degeneration provides a possible explanation for hub vulnerability in Alzheimer's disease, supported by the observed relation between connectivity and activity and the reproduction of several neurophysiologic hallmarks. The insight that neuronal activity might play a causal role in Alzheimer's disease can have implications for early detection and interventional strategies.

Project description:Neurodegenerative diseases such as Alzheimer's disease (AD) exhibit pathological changes in the brain that proceed in a stereotyped and regionally specific fashion, but the cellular and molecular underpinnings of regional vulnerability are currently poorly understood. Recent work has identified certain subpopulations of neurons in a few focal regions of interest, such as the entorhinal cortex, that are selectively vulnerable to tau pathology in AD. However, the cellular underpinnings of regional susceptibility to tau pathology are currently unknown, primarily because whole-brain maps of a comprehensive collection of cell types have been inaccessible. Here, we deployed a recent cell-type mapping pipeline, Matrix Inversion and Subset Selection (MISS), to determine the brain-wide distributions of pan-hippocampal and neocortical neuronal and non-neuronal cells in the mouse using recently available single-cell RNA sequencing (scRNAseq) data. We then performed a robust set of analyses to identify general principles of cell-type-based selective vulnerability using these cell-type distributions, utilizing 5 transgenic mouse studies that quantified regional tau in 12 distinct PS19 mouse models. Using our approach, which constitutes the broadest exploration of whole-brain selective vulnerability to date, we were able to discover cell types and cell-type classes that conferred vulnerability and resilience to tau pathology. Hippocampal glutamatergic neurons as a whole were strongly positively associated with regional tau deposition, suggesting vulnerability, while cortical glutamatergic and GABAergic neurons were negatively associated. Among glia, we identified oligodendrocytes as the single-most strongly negatively associated cell type, whereas microglia were consistently positively correlated. Strikingly, we found that there was no association between the gene expression relationships between cell types and their vulnerability or resilience to tau pathology. When we looked at the explanatory power of cell types versus GWAS-identified AD risk genes, cell type distributions were consistently more predictive of end-timepoint tau pathology than regional gene expression. To understand the functional enrichment patterns of the genes that were markers of the identified vulnerable or resilient cell types, we performed gene ontology analysis. We found that the genes that are directly correlated to tau pathology are functionally distinct from those that constitutively embody the vulnerable cells. In short, we have demonstrated that regional cell-type composition is a compelling explanation for the selective vulnerability observed in tauopathic diseases at a whole-brain level and is distinct from that conferred by risk genes. These findings may have implications in identifying cell-type-based therapeutic targets.

Dataset Information

Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability.

Publications

Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability.

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