Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer's Disease Progression

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 Feb 11

PMID 36768235

Authors

Felicia Liana Andronie-Cioara

Adriana Ioana Ardelean

Carmen Delia Nistor-Cseppento

Anamaria Jurcau

Maria Carolina Jurcau

Nicoleta Pascalau

Florin Marcu

Affiliations

Soon will be listed here.

Abstract

Aging is the most prominent risk factor for late-onset Alzheimer's disease. Aging associates with a chronic inflammatory state both in the periphery and in the central nervous system, the evidence thereof and the mechanisms leading to chronic neuroinflammation being discussed. Nonetheless, neuroinflammation is significantly enhanced by the accumulation of amyloid beta and accelerates the progression of Alzheimer's disease through various pathways discussed in the present review. Decades of clinical trials targeting the 2 abnormal proteins in Alzheimer's disease, amyloid beta and tau, led to many failures. As such, targeting neuroinflammation via different strategies could prove a valuable therapeutic strategy, although much research is still needed to identify the appropriate time window. Active research focusing on identifying early biomarkers could help translating these novel strategies from bench to bedside.

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References

Mecocci P, MacGarvey U, Beal M . Oxidative damage to mitochondrial DNA is increased in Alzheimer's disease. Ann Neurol. 1994; 36(5):747-51. DOI: 10.1002/ana.410360510. View

Camacho-Pereira J, Tarrago M, Chini C, Nin V, Escande C, Warner G . CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism. Cell Metab. 2016; 23(6):1127-1139. PMC: 4911708. DOI: 10.1016/j.cmet.2016.05.006. View

Blennow K, Shaw L, Stomrud E, Mattsson N, Toledo J, Buck K . Predicting clinical decline and conversion to Alzheimer's disease or dementia using novel Elecsys Aβ(1-42), pTau and tTau CSF immunoassays. Sci Rep. 2019; 9(1):19024. PMC: 6911086. DOI: 10.1038/s41598-019-54204-z. View

Curdy N, Lanvin O, Laurent C, Fournie J, Franchini D . Regulatory Mechanisms of Inhibitory Immune Checkpoint Receptors Expression. Trends Cell Biol. 2019; 29(10):777-790. DOI: 10.1016/j.tcb.2019.07.002. View

Jurk D, Wang C, Miwa S, Maddick M, Korolchuk V, Tsolou A . Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell. 2012; 11(6):996-1004. PMC: 3533793. DOI: 10.1111/j.1474-9726.2012.00870.x. View

Lim F, Hernandez F, Lucas J, Gomez-Ramos P, Moran M, Avila J . FTDP-17 mutations in tau transgenic mice provoke lysosomal abnormalities and Tau filaments in forebrain. Mol Cell Neurosci. 2001; 18(6):702-14. DOI: 10.1006/mcne.2001.1051. View

Jara C, Aranguiz A, Cerpa W, Tapia-Rojas C, Quintanilla R . Genetic ablation of tau improves mitochondrial function and cognitive abilities in the hippocampus. Redox Biol. 2018; 18:279-294. PMC: 6072970. DOI: 10.1016/j.redox.2018.07.010. View

Hou Y, Wei Y, Lautrup S, Yang B, Wang Y, Cordonnier S . NAD supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease via cGAS-STING. Proc Natl Acad Sci U S A. 2021; 118(37). PMC: 8449423. DOI: 10.1073/pnas.2011226118. View

Wang Y, Zhang N, Zhang L, Li R, Fu W, Ma K . Autophagy Regulates Chromatin Ubiquitination in DNA Damage Response through Elimination of SQSTM1/p62. Mol Cell. 2016; 63(1):34-48. DOI: 10.1016/j.molcel.2016.05.027. View

10.

Rabinovici G, Gatsonis C, Apgar C, Chaudhary K, Gareen I, Hanna L . Association of Amyloid Positron Emission Tomography With Subsequent Change in Clinical Management Among Medicare Beneficiaries With Mild Cognitive Impairment or Dementia. JAMA. 2019; 321(13):1286-1294. PMC: 6450276. DOI: 10.1001/jama.2019.2000. View

11.

Ojala J, Sutinen E . The Role of Interleukin-18, Oxidative Stress and Metabolic Syndrome in Alzheimer's Disease. J Clin Med. 2017; 6(5). PMC: 5447946. DOI: 10.3390/jcm6050055. View

12.

Griciuc A, Serrano-Pozo A, Parrado A, Lesinski A, Asselin C, Mullin K . Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron. 2013; 78(4):631-43. PMC: 3706457. DOI: 10.1016/j.neuron.2013.04.014. View

13.

Li J, Huang J, Jeong J, Park S, Wei R, Peng J . Selective TBK1/IKKi dual inhibitors with anticancer potency. Int J Cancer. 2013; 134(8):1972-80. PMC: 3947486. DOI: 10.1002/ijc.28507. View

14.

Dempsey C, Rubio Araiz A, Bryson K, Finucane O, Larkin C, Mills E . Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav Immun. 2016; 61:306-316. DOI: 10.1016/j.bbi.2016.12.014. View

15.

de Oliveira J, Kucharska E, Garcez M, Rodrigues M, Quevedo J, Moreno-Gonzalez I . Inflammatory Cascade in Alzheimer's Disease Pathogenesis: A Review of Experimental Findings. Cells. 2021; 10(10). PMC: 8533897. DOI: 10.3390/cells10102581. View

16.

Bursavich M, Harrison B, Blain J . Gamma Secretase Modulators: New Alzheimer's Drugs on the Horizon?. J Med Chem. 2016; 59(16):7389-409. DOI: 10.1021/acs.jmedchem.5b01960. View

17.

Chan S, Mayne M, Holden C, Geiger J, Mattson M . Presenilin-1 mutations increase levels of ryanodine receptors and calcium release in PC12 cells and cortical neurons. J Biol Chem. 2000; 275(24):18195-200. DOI: 10.1074/jbc.M000040200. View

18.

Kensler T, Wakabayashi N, Biswal S . Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol. 2006; 47:89-116. DOI: 10.1146/annurev.pharmtox.46.120604.141046. View

19.

Mecocci P, Boccardi V, Cecchetti R, Bastiani P, Scamosci M, Ruggiero C . A Long Journey into Aging, Brain Aging, and Alzheimer's Disease Following the Oxidative Stress Tracks. J Alzheimers Dis. 2018; 62(3):1319-1335. PMC: 5870006. DOI: 10.3233/JAD-170732. View

20.

Pickett E, Herrmann A, McQueen J, Abt K, Dando O, Tulloch J . Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease. Cell Rep. 2019; 29(11):3592-3604.e5. PMC: 6915767. DOI: 10.1016/j.celrep.2019.11.044. View