NDLI: Cell Signaling Abnormalities May Drive Neurodegeneration in Familial Alzheimer Disease

Please wait, while we are loading the content...

The Odyssey of a Young Gene: Structure–Function Studies in Human Glutamate Dehydrogenases Reveal Evolutionary-Acquired Complex Allosteric Regulation Mechanisms

Glutamate Dehydrogenase Isoforms with N-Terminal (His)$_{6}$- or FLAG-Tag Retain Their Kinetic Properties and Cellular Localization

Heterogeneous Cellular Distribution of Glutamate Dehydrogenase in Brain and in Non-neural Tissues

Intertissue Differences for the Role of Glutamate Dehydrogenase in Metabolism

Imine Reductases: A Comparison of Glutamate Dehydrogenase to Ketimine Reductases in the Brain

Mitochondrial Biogenesis and Dynamics in Neurodegeneration: A Causative Relationship

Common Players in Mitochondria Biogenesis and Neuronal Protection Against Stress-Induced Apoptosis

Neuron–Astrocyte Interactions, Pyruvate Carboxylation and the Pentose Phosphate Pathway in the Neonatal Rat Brain

Cell Signaling Abnormalities May Drive Neurodegeneration in Familial Alzheimer Disease

The Neurobiology of LRRK2 and its Role in the Pathogenesis of Parkinson’s Disease

Glutamine in the Pathogenesis of Hepatic Encephalopathy: The Trojan Horse Hypothesis Revisited

Roles of Changes in Active Glutamine Transport in Brain Edema Development During Hepatic Encephalopathy: An Emerging Concept

Expression of Glutamate Decarboxylase (GAD) mRNA in the Brain of Bile Duct Ligated Rats Serving as a Model of Hepatic Encephalopathy

Neurochemical Research : Volume 39, Issue 2, February 2014

Neurochemical Research : Volume 39, Issue 1, January 2014

Neurochemical Research : Volume 38

Neurochemical Research : Volume 37

Neurochemical Research : Volume 36

Neurochemical Research : Volume 35

Neurochemical Research : Volume 34

Neurochemical Research : Volume 33

Neurochemical Research : Volume 32

Neurochemical Research : Volume 31

Neurochemical Research : Volume 30

Neurochemical Research : Volume 29

Neurochemical Research : Volume 28

Neurochemical Research : Volume 27

Neurochemical Research : Volume 26

Neurochemical Research : Volume 25

Neurochemical Research : Volume 24

Neurochemical Research : Volume 23

Neurochemical Research : Volume 22

Cell Signaling Abnormalities May Drive Neurodegeneration in Familial Alzheimer Disease

Content Provider	Springer Nature Link
Author	Robakis, Nikolaos K.
Copyright Year	2013
Abstract	Presenilins (PSs) are catalytic components of the γ-secretase complex that produces Aβ peptides. Substrates of γ-secretase are membrane-bound protein fragments deriving from the cleavage of extracellular sequence of cell surface proteins. APP-derived γ-secretase substrates are cleaved at gamma (γ) sites to produce Aβ while cleavage at the epsilon (ε) site produces AICD proposed to function in transcription. In addition to APP, γ-secretase promotes the ε-cleavage of a large number of cell surface proteins producing cytosolic peptides shown to function in cell signaling. A common hypothesis suggests that Alzheimer’s disease (AD) is caused by Aβ peptides or their products. Treatment of patients with inhibitors of Aβ production however, showed no therapeutic benefits while inducing cytotoxicity. Similarly, treatments with anti-Aβ antibodies yielded disappointing results. Importantly, recent evidence shows that PS familial AD (FAD) mutations cause a loss of γ-secretase cleavage activity at ε site of substrates thus inhibiting production of biologically important cell signaling peptides while promoting accumulation of membrane-bound cytotoxic substrates. These data support a hypothesis that FAD mutations may increase neurotoxicity by inhibiting the γ-secretase-catalyzed ε cleavage of substrates thus interfering with cell signaling while also promoting accumulation of cytotoxic peptides. Similar mechanisms may explain γ-secretase inhibitor-associated toxicities observed in clinical trials. Here we discuss evidence that FAD neurodegeneration may be caused by loss of γ-secretase cleavage function at ε sites of substrates.
Starting Page	570
Ending Page	575
Page Count	6
File Format	PDF
ISSN	03643190
Journal	Neurochemical Research
Volume Number	39
Issue Number	3
e-ISSN	15736903
Language	English
Publisher	Springer US
Publisher Date	2013-02-23
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Epsilon cleavage γ-Secretase loss of function Signal transduction Neurosciences Neurochemistry Biochemistry Cell Biology Neurology
Content Type	Text
Resource Type	Article
Subject	Medicine Biochemistry Cellular and Molecular Neuroscience

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Cell signaling abnormalities may drive neurodegeneration in Familial Alzheimer disease

A Presenilin-1 Mutation Identified in Familial Alzheimer Disease with Cotton Wool Plaques Causes a Nearly Complete Loss of γ-Secretase Activity

MH84: A Novel γ-Secretase Modulator/PPARγ Agonist—Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer’s Disease

Brain Ischemia Activates β- and γ-Secretase Cleavage of Amyloid Precursor Protein: Significance in Sporadic Alzheimer’s Disease

Activation of Amyloid Precursor Protein Processing by Growth Factors is Dependent on Ras GTPase Activity

Hydrogen Sulfide Selectively Inhibits γ-Secretase Activity and Decreases Mitochondrial Aβ Production in Neurons from APP/PS1 Transgenic Mice

Effects of Aluminium on β-Amyloid (1–42) and Secretases (APP-Cleaving Enzymes) in Rat Brain

The γ-Secretase Modulator CHF5074 Reduces the Accumulation of Native Hyperphosphorylated Tau in a Transgenic Mouse Model of Alzheimer’s Disease

Overlooked Alzheimer’s Smoking Gun?

Cell Signaling Abnormalities May Drive Neurodegeneration in Familial Alzheimer Disease

Similar Documents

Cell signaling abnormalities may drive neurodegeneration in Familial Alzheimer disease

A Presenilin-1 Mutation Identified in Familial Alzheimer Disease with Cotton Wool Plaques Causes a Nearly Complete Loss of γ-Secretase Activity

MH84: A Novel γ-Secretase Modulator/PPARγ Agonist—Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer’s Disease

Brain Ischemia Activates β- and γ-Secretase Cleavage of Amyloid Precursor Protein: Significance in Sporadic Alzheimer’s Disease

Activation of Amyloid Precursor Protein Processing by Growth Factors is Dependent on Ras GTPase Activity

Hydrogen Sulfide Selectively Inhibits γ-Secretase Activity and Decreases Mitochondrial Aβ Production in Neurons from APP/PS1 Transgenic Mice

Effects of Aluminium on β-Amyloid (1–42) and Secretases (APP-Cleaving Enzymes) in Rat Brain

The γ-Secretase Modulator CHF5074 Reduces the Accumulation of Native Hyperphosphorylated Tau in a Transgenic Mouse Model of Alzheimer’s Disease

Overlooked Alzheimer’s Smoking Gun?

Cell Signaling Abnormalities May Drive Neurodegeneration in Familial Alzheimer Disease