Abstract
Ceramides are lipid signaling molecules that cause cytotoxicity and cell death mediated by insulin resistance, inflammation, and endoplasmic reticulum (ER) stress. However, insulin resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and ER stress. Herein, we discuss two major pathways, extrinsic and intrinsic, that converge and often overlap in propagating AD-type neurodegeneration via a triangulated mal-signaling network. First, we review evidence that systemic insulin resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. Mechanistically, we propose that toxic ceramides generated in extra-CNS tissues (e.g., liver) get released into peripheral blood, and subsequently transit across the blood-brain barrier into the brain where they induce brain insulin resistance, inflammation, and cell death (extrinsic pathway). Then we discuss the role of the intrinsic pathway of neurodegeneration which is mediated by endogenous or primary brain insulin/IGF resistance, and impairs neuronal and oligodendrocyte survival, energy metabolism, membrane integrity, cytoskeletal function, and AβPP-Aβ secretion. The end result is increas...Continue Reading
Citations
Jul 3, 2015·Frontiers in Neuroscience·Gaurav BedseTommaso Cassano
Apr 23, 2013·Clinical Lipidology·Michelle M Mielke, Norman J Haughey
Mar 23, 2018·Journal of Alzheimer's Disease : JAD·Julia R ClarkeMychael V Lourenco
Mar 23, 2018·Journal of Alzheimer's Disease : JAD·Suzanne M de la MonteJack R Wands
Feb 23, 2017·Scientific Reports·Debra J SkeneA Jennifer Morton
Sep 21, 2018·PloS One·Ishan PatilEnrique Cadenas
Feb 6, 2018·Lipids in Health and Disease·Caixia RenYuxin Yin
Jan 1, 2013·Brain Sciences·Mariko Saito, Mitsuo Saito
Jan 25, 2014·International Journal of Experimental Pathology·Ming TongSuzanne M de la Monte
Nov 13, 2013·Expert Opinion on Drug Delivery·Suzanne M de la Monte
Jun 17, 2014·Diabetes·Fernanda G De Felice, Sergio T Ferreira
May 30, 2015·PloS One·Zhigang LiuEnrique Cadenas
Dec 8, 2015·Molecular Brain·Kiwamu WatanabeAyae Kinoshita
Sep 25, 2015·Journal of Alzheimer's Disease : JAD·Daniel ÅbergJohan Svensson
Feb 3, 2016·Journal of Alzheimer's Disease : JAD·Kavin NunezSuzanne M de la Monte
Feb 18, 2014·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Sergio T FerreiraFernanda G De Felice
Jul 15, 2015·Scientific Reports·Thanh-Phuong NguyenLaura Caberlotto
Mar 16, 2017·PloS One·Ayse BatovaAlice L Yu
Aug 22, 2015·The Journal of Physiology·Fei YinEnrique Cadenas
May 11, 2016·Endocrine·Sebastian BertramChristian Brinkmann
Apr 18, 2018·Journal of Alzheimer's Disease : JAD·Timothy A CouttasAnthony S Don
Feb 26, 2013·Journal of Molecular Neuroscience : MN·Masoumeh Asle-RoustaLeila Dargahi
Jul 28, 2020·JAD Reports·Owen Sanders, Lekshmy Rajagopal
Aug 4, 2020·American Journal of Physiology. Endocrinology and Metabolism·Nicole ZeltserMagdalena Maj
Oct 22, 2014·Journal of Lipid Research·Aikaterini AlexakiRichard L Proia
Jan 27, 2019·Journal of Neuroinflammation·Marta A MałkiewiczPaweł J Winklewski
Dec 16, 2018·Metabolic Brain Disease·Zahra AbbasnejadRasoul Ghasemi
May 14, 2019·ASN Neuro·Connie J LiouSuzanne M de la Monte
May 30, 2020·JAD Reports·Owen Sanders
Jun 18, 2021·Bioorganic & Medicinal Chemistry Letters·Muhammed AlzweiriL M Viranga Tillekeratne