Cilostazol restores autophagy flux in bafilomycin A1-treated, cultured cortical astrocytes through lysosomal reacidification: roles of PKA, zinc and metallothionein 3.

Scientific Reports
Ha Na KimJae-Young Koh

Abstract

Cilostazol, a phosphodiesterase 3 inhibitor, reduces the amyloid-beta (Aβ) burden in mouse models of Alzheimer disease by as yet unidentified mechanisms. In the present study, we examined the possibility that cilostazol ameliorates lysosomal dysfunction. Astrocytes treated with bafilomycin A1 (BafA1) exhibited markedly reduced DND-189 and acridine orange (AO) fluorescence, indicating reduced lysosomal acidity. In both cases, BafA1-induced alkalization was reversed by addition of cilostazol, dibutyryl cAMP or forskolin. All three agents significantly increased free zinc levels in lysosomes, and addition of the zinc chelator TPEN abrogated lysosomal reacidification. These treatments did not raise free zinc levels or reverse BafA1-mediated lysosomal alkalization in metallothionein 3 (Mt3)-null astrocytes, indicating that the increases in zinc in astrocytes were derived mainly from Mt3. Lastly, in FITC-Aβ-treated astrocytes, cilostazol reversed lysosomal alkalization, increased cathepsin D activity, and reduced Aβ accumulation in astrocytes. Cilostazol also reduced mHtt aggregate formation in GFP-mHttQ74-expressing astrocytes. Collectively, our results present the novel finding that cAMP/PKA can overcome the v-ATPase blocking effec...Continue Reading

References

Jul 24, 2004·Nature Medicine·Christopher A Ross, Michelle A Poirier
Jan 22, 2005·The Journal of Biological Chemistry·Jung Jin HwangJae-Young Koh
Mar 9, 2005·Journal of Neuropathology and Experimental Neurology·Ralph A NixonAna Maria Cuervo
Mar 16, 2006·Proceedings of the National Academy of Sciences of the United States of America·Petra DamesOtto Baumann
Apr 29, 2006·Stroke; a Journal of Cerebral Circulation·Terubumi WatanabeTakao Urabe
Jul 25, 2006·Trends in Neurosciences·Ralph A Nixon
Mar 31, 2007·Nature Reviews. Drug Discovery·David C RubinszteinDaniel J Klionsky
Apr 3, 2009·Biochimica Et Biophysica Acta·Zhenyu YueKeiji Tanaka
Apr 15, 2010·Molecular Neurodegeneration·Lonnie Schneider, Jianhua Zhang
Jun 19, 2010·PloS One·Philipp A JaegerTony Wyss-Coray
Sep 10, 2010·British Journal of Pharmacology·Masayuki HiramatsuHiromasa Mori
Oct 13, 2010·Archives of Neurology·Philipp A Jaeger, Tony Wyss-Coray
Jan 5, 2011·Journal of Cardiovascular Medicine·Natnicha KanlopNipon Chattipakorn
Jun 18, 2011·Arteriosclerosis, Thrombosis, and Vascular Biology·Wei-Jan ChenYung-Hsin Yeh
Jul 30, 2011·Stroke; a Journal of Cerebral Circulation·Naoki OyamaKazuo Kitagawa
Dec 14, 2011·Neurochemistry International·Ha Na KimJae-Young Koh
Aug 7, 2013·Journal of Molecular Cell Biology·Hanna AppelqvistKarin Öllinger
Nov 1, 2013·Alzheimer's Research & Therapy·Miranda E Orr, Salvatore Oddo
Nov 22, 2013·Biochemical Society Transactions·MaryKate McBrayer, Ralph A Nixon
Dec 3, 2014·Journal of Cell Science·Michelle E Maxson, Sergio Grinstein
Mar 15, 2015·Experimental & Molecular Medicine·Aaron Ciechanover, Yong Tae Kwon
Jun 15, 2015·Biochimica Et Biophysica Acta·Ge-Hong Sun-Wada, Yoh Wada
Jun 24, 2015·The Journal of Experimental Medicine·David C RubinszteinVojo Deretic
Oct 9, 2015·Translational Neurodegeneration·Yong-Bo HuGang Wang
Feb 26, 2016·Biochimica Et Biophysica Acta·Christina McGuireMichael Forgac
Apr 4, 2016·Brain Research·Sandra Maday
May 20, 2016·Ageing Research Reviews·Daniel J Colacurcio, Ralph A Nixon
Jul 7, 2016·Journal of Pharmacological Sciences·Toshinori Takagi, Hideaki Hara
Dec 13, 2016·Toxicology and Applied Pharmacology·Jeong A ChoiYoung Hee Yoon
Mar 11, 2017·Neuron·Fiona M MenziesDavid C Rubinsztein
Mar 16, 2017·Translational Neurodegeneration·Patrick SweeneyRobert Hodgson

❮ Previous
Next ❯

Citations

Aug 29, 2020·Cells·Muhammad Aslam, Yury Ladilov
Jun 3, 2021·Cells·Rena KonoRyuta Koyama
Jul 3, 2021·Pharmaceutics·Olja MijanovicAndrey A Zamyatnin

❮ Previous
Next ❯

Methods Mentioned

BETA
Fluorescence
fluorescence microscopy
transfection
Protein Assay
confocal microscopy

Software Mentioned

Sigma Plot
Prism
Zen
Image J

Related Concepts

Related Feeds

Autophagy & Disease

Autophagy is an important cellular process for normal physiology and both elevated and decreased levels of autophagy are associated with disease. Here is the latest research.

Alzheimer's Disease: Endosomes

Dysfunctional endosomal trafficking may be associated with Alzheimer’s disease (AD) pathology. Targeting the endosome may advance treatment options for AD. Here is the latest research on endosomes and AD.

Autophagy & Model Organisms

Autophagy is a cellular process that allows degradation by the lysosome of cytoplasmic components such as proteins or organelles. Here is the latest research on autophagy & model organisms

Alzheimer's Disease: Animal Models

Alzheimer's disease is a neurodegenerative disease which can be studied using various experimental systems. This feed focuses on animal models used for Alzheimer's disease research.

Astrocytes & Amyloid

Astrocytes are thought to play a role in amyloid production and have been implicated in neurodegenerative diseases such as Alzheimer’s disease. Here is the latest research on the relationship between astrocytes and amyloid.

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.

Astrocytes

Astrocytes are glial cells that support the blood-brain barrier, facilitate neurotransmission, provide nutrients to neurons, and help repair damaged nervous tissues. Here is the latest research.

Related Papers

Nihon rinsho. Japanese journal of clinical medicine
Haruo Hirayama
American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists
Nihon rinsho. Japanese journal of clinical medicine
Teruo Inoue
© 2022 Meta ULC. All rights reserved