Triangulated mal-signaling in Alzheimer's disease: roles of neurotoxic ceramides, ER stress, and insulin resistance reviewed.

Journal of Alzheimer's Disease : JAD
Suzanne M de la Monte

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
Feb 23, 2017·Scientific Reports·Debra J SkeneA Jennifer Morton
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
Sep 25, 2015·Journal of Alzheimer's Disease : JAD·Daniel ÅbergJohan Svensson
Feb 18, 2014·Alzheimer's & Dementia : the Journal of the Alzheimer's Association·Sergio T FerreiraFernanda G De Felice
Aug 22, 2015·The Journal of Physiology·Fei YinEnrique Cadenas
Feb 26, 2013·Journal of Molecular Neuroscience : MN·Masoumeh Asle-RoustaLeila Dargahi
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
Jun 18, 2021·Bioorganic & Medicinal Chemistry Letters·Muhammed AlzweiriL M Viranga Tillekeratne

❮ Previous
Next ❯

Related Concepts

Related Feeds

Blood Brain Barrier & Cytokines

Some cytokines are able to cross the blood brain barrier through transport systems and enter the cerebrospinal fluid and interstitial fluid spaces. Here is the latest research on cytokines crossing the blood brain barrier and how this can affect tissues within the CNS.

Blood Brain Barrier

The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.

Blood Brain Barrier Regulation in Health & Disease

The blood brain barrier is essential in regulating the movement of molecules and substances in and out of the brain. Disruption to the blood brain barrier and changes in permeability allow pathogens and inflammatory molecules to cross the barrier and may play a part in the pathogenesis of neurodegenerative disorders. Here is the latest research in this field.

Blood Brain Barrier Chips

The blood brain barrier (BBB) is comprised of endothelial cells that regulate the influx and outflux of plasma concentrations. Lab-on-a-chip devices allow scientists to model diseases and mechanisms such as the passage of therapeutic antibodies across the BBB. Discover the latest research on BBB chips here.