Multiscale causal networks identify VGF as a key regulator of Alzheimer’s disease

Abstract

Though discovered over 100 years ago, the molecular foundation of sporadic Alzheimer's disease (AD) remains elusive. To better characterize the complex nature of AD, we constructed multiscale causal networks on a large human AD multi-omics dataset, integrating clinical features of AD, DNA variation, and gene-and protein-expression. These probabilistic causal models enabled detection, prioritization and replication of high-confidence master regulators of AD-associated networks, including the top predicted regulator, VGF. Overexpression of neuropeptide precursor VGF in 5xFAD mice partially rescued beta-amyloid-mediated memory impairment and neuropathology. Molecular validation of network predictions downstream of VGF was also achieved in this AD model, with significant enrichment for homologous genes identified as differentially expressed in 5xFAD brains overexpressing VGF. Our findings support a causal role for VGF in protecting against AD pathogenesis and progression.

Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF

“…Yet, a close correlation between NPTX2 and VGF was observed in cognitively healthy subjects, and this was maintained in both DLB and in AD, although somewhat weaker. Recently, VGF has been implicated as a master regulator of NPTX2 and BDNF [ 28 ], where BDNF itself also functions as regulator of both NPTX2 and VGF [ 18 , 26 ]. In this process, BDNF and VGF are seen as key regulators of neurogenesis, synaptic plasticity, and cognition [ 28 ].…”

“…The other candidate biomarker in the DLB proteomics study, VGF, is an interesting marker to compare to NPTX2, as its transcription is induced by neuronal growth factor (NGF) and BDNF [ 26 , 27 ]. This BDNF pathway is impacted in neurodegeneration, and VGF was implicated as a master regulator for NPTX2 [ 28 ]. VGF peptides are stored in dense core vesicles (DCVs), function as secretory peptide at synapses, and are important for a number of neuronal functions [ 27 , 29 ].…”

“…A detailed study into the role of VGF peptide GGEE45 has shown decreased CSF levels in DLB patients and levels correlated to cognitive decline in multiple cognitive domains [ 30 ]. VGF has also been implicated as an AD biomarker and changes in relation to disease progression [ 28 , 31 ]. Therefore, the relation between VGF and NPTX2 levels in CSF might give insight into changes in VGF/BDNF driven synaptic functioning and dysfunction under pathological conditions.…”

Predictive network modeling in human induced pluripotent stem cells identifies key driver genes for insulin responsiveness

“…K = 6 was used in this paper. This cutoff was chosen based on practical considerations (K will depend on the size and complexity of the network) and while we can use other cut-offs, K = 6 is commonly used in previous studies and is the default value suggested in the KDA software [ 9 , 26 , 83 , 84 ]. This K value is preferred because the key drivers within K steps can all be detected.…”

Glia in Neurodegeneration: The Housekeeper, the Defender and the Perpetrator

“…Genetic analysis, epidemiological studies, gene expression, and imaging in human patients demonstrate the contribution of glial cell dysfunction to neurodegeneration (Table S2). Genetic analysis using genome-wide associated studies identified a link between immune response and risk for AD [83]. Additionally, epidemiological studies linking the use of anti-inflammatory drugs with a decreased risk for dementia suggested that inflammation may be a contributing factor [84].…”