Liquid Biopsy in Alzheimer's Disease Patients Reveals Epigenetic Changes in the Gene

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2023 Dec 9

PMID 38067107

Authors

Monica Macias

Blanca Acha

Jon Corroza

Amaya Urdanoz-Casado

Miren Roldan

Maitane Robles

Javier Sanchez-Ruiz de Gordoa

Maria Elena Erro

Ivonne Jerico

Idoia Blanco-Luquin

Maite Mendioroz

Affiliations

Soon will be listed here.

Abstract

In recent years, new DNA methylation variants have been reported in genes biologically relevant to Alzheimer's disease (AD) in human brain tissue. However, this AD-specific epigenetic information remains brain-locked and unreachable during patients' lifetimes. In a previous methylome performed in the hippocampus of 26 AD patients and 12 controls, we found higher methylation levels in AD patients in the promoter region of , a gene involved in energy balance regulation. Our aim was to further characterize 's role in AD and to evaluate if the liquid biopsy technique would provide life access to this brain information in a non-invasive way. First, we extended the methylation mapping of and validated previous methylome results via bisulfite cloning sequencing. Next, we observed a positive correlation between methylation levels and AD-related neuropathological changes and a decreased expression of in AD hippocampus. Then, we managed to replicate the hippocampal methylation differences in plasma cfDNA from an additional cohort of 35 AD patients and 35 controls. The isolation of cfDNA from the plasma of AD patients may constitute a source of potential epigenetic biomarkers to aid AD clinical management.

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References

Lunnon K, Smith R, Hannon E, De Jager P, Srivastava G, Volta M . Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nat Neurosci. 2014; 17(9):1164-70. PMC: 4410018. DOI: 10.1038/nn.3782. View

de Mendoza A, Poppe D, Buckberry S, Pflueger J, Albertin C, Daish T . The emergence of the brain non-CpG methylation system in vertebrates. Nat Ecol Evol. 2021; 5(3):369-378. PMC: 7116863. DOI: 10.1038/s41559-020-01371-2. View

Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A . Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol. 2013; 10(8):472-84. DOI: 10.1038/nrclinonc.2013.110. View

Holubova M, Hruba L, Popelova A, Bencze M, Prazienkova V, Gengler S . Liraglutide and a lipidized analog of prolactin-releasing peptide show neuroprotective effects in a mouse model of β-amyloid pathology. Neuropharmacology. 2018; 144:377-387. DOI: 10.1016/j.neuropharm.2018.11.002. View

Smith A, Smith R, Condliffe D, Hannon E, Schalkwyk L, Mill J . Increased DNA methylation near TREM2 is consistently seen in the superior temporal gyrus in Alzheimer's disease brain. Neurobiol Aging. 2016; 47:35-40. PMC: 5747529. DOI: 10.1016/j.neurobiolaging.2016.07.008. View

Selman A, Burns S, Reddy A, Culberson J, Reddy P . The Role of Obesity and Diabetes in Dementia. Int J Mol Sci. 2022; 23(16). PMC: 9408882. DOI: 10.3390/ijms23169267. View

. Quantitative comparison of DNA methylation assays for biomarker development and clinical applications. Nat Biotechnol. 2016; 34(7):726-37. DOI: 10.1038/nbt.3605. View

Monti N, Cavallaro R, Stoccoro A, Nicolia V, Scarpa S, Kovacs G . CpG and non-CpG Presenilin1 methylation pattern in course of neurodevelopment and neurodegeneration is associated with gene expression in human and murine brain. Epigenetics. 2020; 15(8):781-799. PMC: 7518704. DOI: 10.1080/15592294.2020.1722917. View

Snyder M, Kircher M, Hill A, Daza R, Shendure J . Cell-free DNA Comprises an In Vivo Nucleosome Footprint that Informs Its Tissues-Of-Origin. Cell. 2016; 164(1-2):57-68. PMC: 4715266. DOI: 10.1016/j.cell.2015.11.050. View

10.

Gaitsch H, Franklin R, Reich D . Cell-free DNA-based liquid biopsies in neurology. Brain. 2022; 146(5):1758-1774. PMC: 10151188. DOI: 10.1093/brain/awac438. View

11.

Mrazikova L, Hojna S, Pacesova A, Hruba L, Strnadova V, Neprasova B . Palmitoylated prolactin-releasing peptide treatment had neuroprotective but not anti-obesity effect in fa/fa rats with leptin signaling disturbances. Nutr Diabetes. 2022; 12(1):26. PMC: 9119973. DOI: 10.1038/s41387-022-00205-3. View

12.

Kumaki Y, Oda M, Okano M . QUMA: quantification tool for methylation analysis. Nucleic Acids Res. 2008; 36(Web Server issue):W170-5. PMC: 2447804. DOI: 10.1093/nar/gkn294. View

13.

Nguyen T, Hoai Ta Q, Nguyen T, Nguyen T, Giau V . Type 3 Diabetes and Its Role Implications in Alzheimer's Disease. Int J Mol Sci. 2020; 21(9). PMC: 7246646. DOI: 10.3390/ijms21093165. View

14.

Sanchez-Mut J, Graff J . Epigenetic Alterations in Alzheimer's Disease. Front Behav Neurosci. 2016; 9:347. PMC: 4681781. DOI: 10.3389/fnbeh.2015.00347. View

15.

Prazienkova V, Popelova A, Kunes J, Maletinska L . Prolactin-Releasing Peptide: Physiological and Pharmacological Properties. Int J Mol Sci. 2019; 20(21). PMC: 6862262. DOI: 10.3390/ijms20215297. View

16.

Chen L, Shen Q, Xu S, Yu H, Pei S, Zhang Y . 5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer's Disease. J Alzheimers Dis. 2021; 85(2):573-585. DOI: 10.3233/JAD-215217. View

17.

Altuna M, Urdanoz-Casado A, de Gordoa J, Zelaya M, Labarga A, Lepesant J . DNA methylation signature of human hippocampus in Alzheimer's disease is linked to neurogenesis. Clin Epigenetics. 2019; 11(1):91. PMC: 6585076. DOI: 10.1186/s13148-019-0672-7. View

18.

Jack Jr C, Bennett D, Blennow K, Carrillo M, Dunn B, Budd Haeberlein S . NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14(4):535-562. PMC: 5958625. DOI: 10.1016/j.jalz.2018.02.018. View

19.

Zenaro E, Piacentino G, Constantin G . The blood-brain barrier in Alzheimer's disease. Neurobiol Dis. 2016; 107:41-56. PMC: 5600438. DOI: 10.1016/j.nbd.2016.07.007. View

20.

Bacalini M, Boattini A, Gentilini D, Giampieri E, Pirazzini C, Giuliani C . A meta-analysis on age-associated changes in blood DNA methylation: results from an original analysis pipeline for Infinium 450k data. Aging (Albany NY). 2015; 7(2):97-109. PMC: 4359692. DOI: 10.18632/aging.100718. View