Associations of VGF with Neuropathologies and Cognitive Health in Older Adults
Corresponding Author
Lei Yu PhD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Address correspondence to Dr Yu, Rush Alzheimer's Disease Center, 1750 W Harrison Street, Suite 1000, Chicago, IL 60612, USA. E-mail: [email protected]
Search for more papers by this authorVladislav A. Petyuk PhD
Pacific Northwest National Laboratory, Richland, Washington, USA
Search for more papers by this authorKatia de Paiva Lopes PhD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorShinya Tasaki PhD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorVilas Menon PhD
Center for Translational and Computational Neuroimmunology, Department of Neurology & Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, USA
Search for more papers by this authorYanling Wang PhD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorJulie A. Schneider MD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Department of Pathology, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorPhilip L. De Jager MD, PhD
Center for Translational and Computational Neuroimmunology, Department of Neurology & Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, USA
Search for more papers by this authorDavid A. Bennett MD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorCorresponding Author
Lei Yu PhD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Address correspondence to Dr Yu, Rush Alzheimer's Disease Center, 1750 W Harrison Street, Suite 1000, Chicago, IL 60612, USA. E-mail: [email protected]
Search for more papers by this authorVladislav A. Petyuk PhD
Pacific Northwest National Laboratory, Richland, Washington, USA
Search for more papers by this authorKatia de Paiva Lopes PhD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorShinya Tasaki PhD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorVilas Menon PhD
Center for Translational and Computational Neuroimmunology, Department of Neurology & Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, USA
Search for more papers by this authorYanling Wang PhD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorJulie A. Schneider MD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Department of Pathology, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorPhilip L. De Jager MD, PhD
Center for Translational and Computational Neuroimmunology, Department of Neurology & Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, USA
Search for more papers by this authorDavid A. Bennett MD
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA
Search for more papers by this authorAbstract
Objective
VGF is proposed as a potential therapeutic target for Alzheimer's (AD) and other neurodegenerative conditions. The cell-type specific and, separately, peptide specific associations of VGF with pathologic and cognitive outcomes remain largely unknown. We leveraged gene expression and protein data from the human neocortex and investigated the VGF associations with common neuropathologies and late-life cognitive decline.
Methods
Community-dwelling older adults were followed every year, died, and underwent brain autopsy. Cognitive decline was captured via annual cognitive testing. Common neurodegenerative and cerebrovascular conditions were assessed during neuropathologic evaluations. Bulk brain RNASeq and targeted proteomics analyses were conducted using frozen tissues from dorsolateral prefrontal cortex of 1,020 individuals. Cell-type specific gene expressions were quantified in a subsample (N = 424) following single nuclei RNASeq analysis from the same cortex.
Results
The bulk brain VGF gene expression was primarily associated with AD and Lewy bodies. The VGF gene association with cognitive decline was in part accounted for by neuropathologies. Similar associations were observed for the VGF protein. Cell-type specific analyses revealed that, while VGF was differentially expressed in most major cell types in the cortex, its association with neuropathologies and cognitive decline was restricted to the neuronal cells. Further, the peptide fragments across the VGF polypeptide resembled each other in relation to neuropathologies and cognitive decline.
Interpretation
Multiple pathways link VGF to cognitive health in older age, including neurodegeneration. The VGF gene functions primarily in neuronal cells and its protein associations with pathologic and cognitive outcomes do not map to a specific peptide. ANN NEUROL 2023;94:232–244
Potential Conflicts of Interest
Nothing to report.
Open Research
Data Availability
The datasets supporting the conclusions of this article can be requested for research purposes via Rush Alzheimer's Disease Center Research Resource Sharing Hub at https://www.radc.rush.edu/.
Supporting Information
| Filename | Description |
|---|---|
| ana26676-sup-0001-supinfo.docxWord 2007 document , 20 KB | Data S1. Supporting information. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Selkoe DJ. Alzheimer's disease is a synaptic failure. Science (New York, NY) 2002; 298: 789–791.
- 2Shankar GM, Li S, Mehta TH, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008; 14: 837–842.
- 3Milnerwood AJ, Raymond LA. Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease. Trends Neurosci 2010; 33: 513–523.
- 4Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci 2013; 14: 7–23.
- 5Ferri GL, Noli B, Brancia C, et al. VGF: an inducible gene product, precursor of a diverse array of neuro-endocrine peptides and tissue-specific disease biomarkers. J Chem Neuroanat 2011; 42: 249–261.
- 6Lewis JE, Brameld JM, Jethwa PH. Neuroendocrine Role for VGF. Front Endocrinol 2015; 6: 3.
- 7Llano DA, Devanarayan P, Devanarayan V. VGF in cerebrospinal fluid combined with conventional biomarkers enhances prediction of conversion from MCI to AD. Alzheimer Dis Assoc Disord 2019; 33: 307–314.
- 8Bai B, Wang X, Li Y, et al. Deep multilayer brain proteomics identifies molecular networks in Alzheimer's disease progression. Neuron 2020; 105: 975–991 e7.
- 9Noda Y, Tanaka M, Nakamura S, et al. Identification of VGF nerve growth factor inducible-producing cells in human spinal cords and expression change in patients with amyotrophic lateral sclerosis. Int J Med Sci 2020; 17: 480–489.
- 10Henderson-Smith A, Corneveaux JJ, De Both M, et al. Next-generation profiling to identify the molecular etiology of Parkinson dementia. Neurol Genet 2016; 2:e75.
- 11Khoonsari PE, Shevchenko G, Herman S, et al. Improved differential diagnosis of Alzheimer's disease by integrating ELISA and Mass spectrometry-based cerebrospinal fluid biomarkers. J Alzheimers Dis 2019; 67: 639–651.
- 12Beckmann ND, Lin W-J, Wang M, et al. Multiscale causal networks identify VGF as a key regulator of Alzheimer's disease. Nat Commun 2020; 11: 1–19.
- 13Wingo AP, Dammer EB, Breen MS, et al. Large-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age. Nat Commun 2019; 10: 1–14.
- 14Quinn JP, Kandigian SE, Trombetta BA, et al. VGF as a biomarker and therapeutic target in neurodegenerative and psychiatric diseases. Brain commun 2021; 3:fcab261.
- 15Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007 Dec 11; 69: 2197–2204.
- 16Rahimi J, Kovacs GG. Prevalence of mixed pathologies in the aging brain. Alzheimers Res Ther 2014; 6: 82.
- 17Lin WJ, Jiang C, Sadahiro M, et al. VGF and its C-terminal peptide TLQP-62 regulate memory formation in hippocampus via a BDNF-TrkB-dependent mechanism. J Neurosci 2015; 35: 10343–10356.
- 18Bozdagi O, Rich E, Tronel S, et al. The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism. J Neurosci 2008; 28: 9857–9869.
- 19Alder J, Thakker-Varia S, Bangasser DA, et al. Brain-derived neurotrophic factor-induced gene expression reveals novel actions of VGF in hippocampal synaptic plasticity. J Neurosci 2003; 23: 10800–10808.
- 20Cho K, Jang YJ, Lee SJ, et al. TLQP-21 mediated activation of microglial BV2 cells promotes clearance of extracellular fibril amyloid-β. Biochem Biophys Res Commun 2020; 524: 764–771.
- 21El Gaamouch F, Audrain M, Lin WJ, et al. VGF-derived peptide TLQP-21 modulates microglial function through C3aR1 signaling pathways and reduces neuropathology in 5xFAD mice. Mol Neurodegener 2020; 15: 4.
- 22Bennett DA, Buchman AS, Boyle PA, et al. Religious orders study and rush memory and aging project. J Alzheimers Dis 2018; 64: S161–S189.
- 23Bennett DA, Schneider JA, Buchman AS, et al. The rush memory and aging project: study design and baseline characteristics of the study cohort. Neuroepidemiology 2005; 25: 163–175.
- 24Bennett DA, Schneider JA, Arvanitakis Z, et al. Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 2006; 66: 1837–1844.
- 25Boyle PA, Wilson RS, Yu L, et al. Much of late life cognitive decline is not due to common neurodegenerative pathologies. Ann Neurol 2013; 74: 478–489.
- 26Schneider JA, Arvanitakis Z, Yu L, et al. Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies. Brain 2012 Oct; 135: 3005–3014.
- 27Nag S, Yu L, Capuano AW, et al. Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease. Ann Neurol 2015; 77: 942–952.
- 28Kapasi A, Yu L, Boyle PA, et al. Limbic-predominant age-related TDP-43 encephalopathy, ADNC pathology, and cognitive decline in aging. Neurology 2020; 95: e1951–e1962.
- 29Schneider JA, Wilson RS, Bienias JL, et al. Cerebral infarctions and the likelihood of dementia from Alzheimer disease pathology. Neurology 2004; 62: 1148–1155.
- 30Boyle PA, Yu L, Nag S, et al. Cerebral amyloid angiopathy and cognitive outcomes in community-based older persons. Neurology 2015; 85: 1930–1936.
- 31Arvanitakis Z, Capuano AW, Leurgans SE, et al. Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study. Lancet Neurol 2016 Aug; 15: 934–943.
- 32Yu L, Tasaki S, Schneider JA, et al. Cortical proteins associated with cognitive resilience in community-dwelling older persons. JAMA Psychiat 2020 Nov 1; 77: 1172–1180.
10.1001/jamapsychiatry.2020.1807 Google Scholar
- 33Tasaki S, Xu J, Avey DR, et al. Inferring protein expression changes from mRNA in Alzheimer's dementia using deep neural networks. Nat Commun 2022; 13: 655.
- 34Fujita M, Gao Z, Zeng L, et al. Cell-subtype specific effects of genetic variation in the aging and Alzheimer cortex. bioRxiv 2022; 2022.11.07.515446.
- 35Zheng GX, Terry JM, Belgrader P, et al. Massively parallel digital transcriptional profiling of single cells. Nat Commun 2017; 8: 1–12.
- 36McGinnis CS, Murrow LM, Gartner ZJ. DoubletFinder: doublet detection in single-cell RNA sequencing data using artificial nearest neighbors. Cell systems 2019; 8: 329–337.e4.
- 37Hao Y, Hao S, Andersen-Nissen E, et al. Integrated analysis of multimodal single-cell data. Cell 2021; 184: 3573–3587.e29.
- 38Law CW, Chen Y, Shi W, Smyth GK. Voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol 2014; 15: R29.
- 39Yu L, Petyuk VA, Gaiteri C, et al. Targeted brain proteomics uncover multiple pathways to Alzheimer's dementia. Ann Neurol 2018; 84: 78–88.
- 40Hendrickson RC, Lee AY, Song Q, et al. High resolution discovery proteomics reveals candidate disease progression markers of Alzheimer's disease in human cerebrospinal fluid. PloS One 2015; 10:e0135365.
- 41MacLean B, Tomazela DM, Shulman N, et al. Skyline: an open source document editor for creating and analyzing targeted proteomics experiments. Bioinformatics 2010; 26: 966–968.
- 42van Steenoven I, Koel-Simmelink MJA, Vergouw LJM, et al. Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach. Mol Neurodegener 2020; 15: 36.
- 43Brancia C, Noli B, Boido M, et al. TLQP peptides in amyotrophic lateral sclerosis: possible blood biomarkers with a neuroprotective role. Neuroscience 2018; 380: 152–163.
- 44van der Ende EL, Meeter LH, Stingl C, et al. Novel CSF biomarkers in genetic frontotemporal dementia identified by proteomics. Ann Clin Transl Neurol 2019; 6: 698–707.
- 45Lu B, Nagappan G, Guan X, et al. BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 2013; 14: 401–416.
- 46Trachtenberg JT, Chen BE, Knott GW, et al. Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 2002; 420: 788–794.
- 47Holtmaat A, Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci 2009; 10: 647–658.
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