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BACE1 activity impairs neuronal glucose oxidation: rescue by beta-hydroxybutyrate and lipoic acid

Findlay, John A., Hamilton, David L. and Ashford, Michael L. J. 2015, BACE1 activity impairs neuronal glucose oxidation: rescue by beta-hydroxybutyrate and lipoic acid, Frontiers in cellular neuroscience, vol. 9, pp. 1-14, doi: 10.3389/fncel.2015.00382.

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Title BACE1 activity impairs neuronal glucose oxidation: rescue by beta-hydroxybutyrate and lipoic acid
Author(s) Findlay, John A.
Hamilton, David L.
Ashford, Michael L. J.
Journal name Frontiers in cellular neuroscience
Volume number 9
Article ID 382
Start page 1
End page 14
Total pages 14
Publisher Frontiers Media
Place of publication Lausanne, Switzerland
Publication date 2015-10
ISSN 1662-5102
Keyword(s) BACE1
alpha lipoic acid
amyloid
glucose metabolism
mitochondria
pyruvate dehydrogenase
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
AMYLOID PRECURSOR PROTEIN
ALZHEIMERS-DISEASE BRAIN
PYRUVATE-DEHYDROGENASE COMPLEX
CYTOCHROME-C-OXIDASE
A-BETA
CLEAVING ENZYME-1
TRANSGENIC MICE
CELL-DEATH
MITOCHONDRIAL ABNORMALITIES
ALPHA-KETOGLUTARATE
Summary Glucose hypometabolism and impaired mitochondrial function in neurons have been suggested to play early and perhaps causative roles in Alzheimer's disease (AD) pathogenesis. Activity of the aspartic acid protease, beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1), responsible for beta amyloid peptide generation, has recently been demonstrated to modify glucose metabolism. We therefore examined, using a human neuroblastoma (SH-SY5Y) cell line, whether increased BACE1 activity is responsible for a reduction in cellular glucose metabolism. Overexpression of active BACE1, but not a protease-dead mutant BACE1, protein in SH-SY5Y cells reduced glucose oxidation and the basal oxygen consumption rate, which was associated with a compensatory increase in glycolysis. Increased BACE1 activity had no effect on the mitochondrial electron transfer process but was found to diminish substrate delivery to the mitochondria by inhibition of key mitochondrial decarboxylation reaction enzymes. This BACE1 activity-dependent deficit in glucose oxidation was alleviated by the presence of beta hydroxybutyrate or α-lipoic acid. Consequently our data indicate that raised cellular BACE1 activity drives reduced glucose oxidation in a human neuronal cell line through impairments in the activity of specific tricarboxylic acid cycle enzymes. Because this bioenergetic deficit is recoverable by neutraceutical compounds we suggest that such agents, perhaps in conjunction with BACE1 inhibitors, may be an effective therapeutic strategy in the early-stage management or treatment of AD.
Language eng
DOI 10.3389/fncel.2015.00382
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2015, Findlay, Hamilton and Ashford
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30112681

Document type: Journal Article
Collections: School of Exercise and Nutrition Sciences
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.