A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology

Fu, Hongjun; Possenti, A.; Freer, Rosie; Nakano, Yoshikazu; Villegas, Nancy C Hernandez; Tang, Maoping; Cauhy, Paula Victoria Maglio; Lassus, Benjamin; Chen, Shuo; Fowler, Stephanie L.; Figueroa, Helen Y.; Huey, Edward D.; Johnson, Gail V.W.; Vendruscolo, Michele; Duff, Karen

doi:10.1038/s41593-018-0298-7

Cited by 188 publications

(176 citation statements)

References 43 publications

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“…This suggests that cell type proposition may have a limited impact on our gene signatures identification. Nonetheless, it is widely accepted that there exists selective regional and cell type-specific vulnerability to LOAD 8,73 . We anticipate generating region-specific singlecell multi-Omics data of LOAD and developing cell type-specific network models will offer invaluable in-depth understanding of the cellular complexity and etiology underlying the devastating disease.…”

Section: Discussionmentioning

confidence: 99%

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Wang

Sekiya

et al. 2019

Preprint

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To study the molecular mechanisms driving the pathogenesis and identify novel therapeutic targets of late onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of whole-genome DNA and RNA sequencing profiling of four cortical areas, including the parahippocampal gyrus, across 364 donors spanning the full spectrum of LOAD-related cognitive and neuropathological disease severities. Our analyses revealed thousands of molecular changes and uncovered for the first-time multiple neuron specific gene subnetworks most dysregulated in LOAD. ATP6V1A, a critical subunit of vacuolar-type H + -ATPase (v-ATPase), was predicted to be a key regulator of one neuronal subnetwork and its role in disease-related processes was evaluated through CRISPR-based manipulation of human induced pluripotent stem cell derived neurons and RNAi-based knockdown in transgenic Drosophila models. This study advances our understanding of LOAD pathogenesis by providing the global landscape and detailed circuits of complex molecular interactions and regulations in several key brain regions affected by LOAD and the resulting network models provide a blueprint for developing next generation therapeutics against LOAD.

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Section: Discussionmentioning

confidence: 99%

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Wang

Sekiya

et al. 2019

Preprint

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“…Standard staining and microscopy techniques were used, as described previously 34,43–45 with some modifications. All washes were done with PBS (1X-PBS containing 0.01% Sodium Azide).…”

Section: Methodsmentioning

confidence: 99%

Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus

Qureshi

Berman

Klein

et al. 2019

Preprint

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Retromer has emerged as a master conductor of endosomal trafficking, and VPS35 and other retromer-related proteins are found to be deficient in late-onset Alzheimer's disease (AD). Depleting VPS35 in neurons impairs retromer function, affecting for example the trafficking of the amyloid-precursor protein (APP) and the glutamate receptor GluA1. Whether VPS35 repletion, after chronic in vivo depletion, can rescue these impairments remains unknown. Here we set out to address this question by using a viral vector approach for VPS35 repletion. First, we completed a series of studies using neuronal cultures in order to optimize AAV9-VPS35 delivery, and to understand how exogenous VPS35 expression affects its endogenous levels as well as its binding to other retromer proteins. Next, we completed a series of studies in wildtype mice to determine the optimum protocol for in vivo delivery of AAV9-VPS35 to the hippocampus. We relied on this information to deliver AAV9-VPS35 to the hippocampus of mice genetically engineered to have chronic, neuronal-selective, VPS35 depletion.VPS35 repletion in the hippocampus was found to normalize APP cleavage and to restore glutamate receptor levels. Unexpectedly, chronic VPS35 depletion in neurons caused glial activation, similar to the pattern observed in AD, which was also partially normalized by VPS35 repletion. Taken together, these studies strengthen the mechanistic link between retromer and AD, and have therapeutic implications.

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“…The spatially varying abundances of cell types considered selectively vulnerable to tau or synuclein inclusions can be mapped using MISS, and their correspondence with the spatial pattern of protein pathologies can be tested. While regional gene expression profiles did not seem especially predictive in a prior analysis 44 , other experiments suggest cell type selectivity of tau pathology [45][46][47] . Cellular vulnerability in other neurological conditions can also be interrogated using MISS, including psychiatric diseases such as schizophrenia 48 , and traumatic brain injury (TBI), which was hypothesized to preferentially involve certain types of cells in both injury and recovery phases 49,50 .…”

Section: Further Potential Applicationsmentioning

confidence: 81%

Matrix Inversion and Subset Selection (MISS): A novel pipeline for mapping of diverse cell types across the murine brain

Mezias

Torok

Maia

et al. 2019

Preprint

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The advent of increasingly sophisticated imaging platforms has allowed for the visualization of the murine nervous system at single-cell resolution. However, current cell counting methods compromise on either the ability to map a large number of different cell types, or spatial coverage, and therefore whole-brain quantification of finely resolved neural cell subtypes remains elusive. Here we present a comprehensive and novel computational pipeline called Matrix Inversion and Subset Selection (MISS) that aims to fill this gap in knowledge and has the ability to infer counts of diverse collections of neural cell types at sub-millimeter resolution using a combination of single-cell RNAseq and in situ hybridization datasets. We rigorously demonstrate the accuracy of MISS against literature expectations, and in so doing, provide the first verified maps for twenty-five distinct neuronal and nonneuronal cell types across the whole mouse brain. The resulting comprehensive cell type maps are uniquely suited to address important open questions in neuroscience. As a demonstration, we utilize our inferred maps to quantitatively establish that adult cell type distributions reflect the ontological splits between brain regions during neural development, indicating that the developmental history of brain regions informs their final cell-type composition. Although this link has been frequently surmised by neuroscientists, its quantitative verification across the entire brain has not previously been demonstrated. Together, our results suggest that the MISS pipeline can be used to generate accurate spatial quantification of diverse cell types without the direct imaging of known type-specific markers, as has been done previously. The entire MISS pipeline and outputs will be made open source in order to catalyze future neuroscientific advances across disciplines.

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A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology

Cited by 188 publications

References 43 publications

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Molecular Networks and Key Regulators of the Dysregulated Neuronal System in Alzheimer’s Disease

Retromer repletion with AAV9-VPS35 restores endosomal function in the mouse hippocampus

Matrix Inversion and Subset Selection (MISS): A novel pipeline for mapping of diverse cell types across the murine brain

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