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

Abstract

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.

Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets

“…Previous work has shown that the hippocampus is strongly associated with A and tau accumulation and early memory loss in AD (24). We have also shown in previous studies of the MSBB-AD cohort that transcriptomic changes in the PHG region highly overlap the Kyoto Encyclopedia of Genes and Genomes (KEGG) (25) Alzheimer's and Parkinson's disease gene sets and are correlated with high A plaque density (19), demonstrating that these changes are consistent with AD disease progression. Therefore, the PHG region carries the strongest molecular signature of AD.…”

“…For example, many protein degradationrelated genes, including ubiquitination and polyubiquitination, protein catabolism, the proteasome, and proteins targeting for destruction, are up-regulated in subtype A while organic acid-related genes, including acid secretion and acidic amino acid transport, are specifically on January 10, 2021 http://advances.sciencemag.org/ Downloaded from up-regulated in class B. Defects in the acidification of lysosomes in neurons have been previously associated with neuronal and synaptic loss in AD, as well as decreases in long-term potentiation (19).…”

“…Some recent studies have highlighted the great advantages of using RNA sequencing (RNA-seq) to profile the transcriptome of the brain with neurodegenerative diseases. For instance, a multiomic molecular analysis of LOAD across four brain regions uncovered subnetworks and previously unidentified molecular drivers of the disease, including the vacuolar adenosine 5′-triphosphate (ATP)dependent proton pump ATP6V1A, which are now shown to modulate cognitive function in Drosophila models of AD (19). In addition, molecular network analysis of LOAD brains has identified an excess of dysregulated genes that cannot be fully predicted by a single model of the disease (19).…”

“…For instance, a multiomic molecular analysis of LOAD across four brain regions uncovered subnetworks and previously unidentified molecular drivers of the disease, including the vacuolar adenosine 5′-triphosphate (ATP)dependent proton pump ATP6V1A, which are now shown to modulate cognitive function in Drosophila models of AD (19). In addition, molecular network analysis of LOAD brains has identified an excess of dysregulated genes that cannot be fully predicted by a single model of the disease (19). Nevertheless, only a limited number of published papers describe RNA-seq studies of the most relevant material, namely, human AD brains across multiple regions (20).…”

Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models

“…Besides synaptic and neuronal loss, AD pathology is also accompanied by changes in astrocytic and microglial cells, and human genome-wide association studies (GWASs) support a causal role for immune mechanisms ( Jansen et al, 2019 ; Kunkle et al, 2019 ; Raj et al, 2014 ). Results from RNA sequencing (RNA-seq) of human postmortem brain tissue further reinforce the importance of microglial and inflammatory mechanisms in AD pathogenesis, among other pathways ( Allen et al, 2018 ; Conway et al, 2018 ; McKenzie et al, 2017 ; Patrick et al, 2017 ; Wang et al, 2016 , 2019 ; Zhang et al, 2013 ).…”