Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease |
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| Authors: | Steven N.Austad Scott Ballinger Thomas W.Buford Christy S.Carter Daniel L.Smith Jr Victor Darley-Usmar Jianhua Zhang |
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| Affiliation: | 1. Department of Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;3. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA;4. Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA |
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| Abstract: | Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts. |
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| Keywords: | Mitochondrial DNA Mitochondrial electron transport chain Mitochondrial quality control Reactive species DAMPs Hexokinase biosynthesis pathway Diabetes Circadian regulation Microbiome alpha-ketoglutarate AD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" Alzheimer's disease ADP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" adenosine diphosphate ADRD" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" AD-related dementias ACE2" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110" }," $$" :[{" #name" :" text" ," _" :" angiotensin I converting enzyme (peptidyl-dipeptidase A) 2 cAMP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0120" }," $$" :[{" #name" :" text" ," _" :" cyclic adenosine monophosphate cGAS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0130" }," $$" :[{" #name" :" text" ," _" :" cyclic GMP/AMP synthase CSF" },{" #name" :" keyword" ," $" :{" id" :" kwrd0140" }," $$" :[{" #name" :" text" ," _" :" cerebrospinal fluid DAMPs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0150" }," $$" :[{" #name" :" text" ," _" :" damage-associated molecular patterns ER" },{" #name" :" keyword" ," $" :{" id" :" kwrd0160" }," $$" :[{" #name" :" text" ," _" :" estrogen receptor ETC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0170" }," $$" :[{" #name" :" text" ," _" :" electron transport chain FCCP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0180" }," $$" :[{" #name" :" text" ," _" :" trifluoromethoxy carbonylcyanide phenylhydrazone PET" },{" #name" :" keyword" ," $" :{" id" :" kwrd0190" }," $$" :[{" #name" :" text" ," _" :" fluorodeoxyglucose (FDG)-positron emission tomography FPR-1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0200" }," $$" :[{" #name" :" text" ," _" :" formyl peptide receptor 1 GIP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0210" }," $$" :[{" #name" :" text" ," _" :" glucose-dependent insulinotropic polypeptide GLP-1" },{" #name" :" keyword" ," $" :{" id" :" kwrd0220" }," $$" :[{" #name" :" text" ," _" :" glucagon-like peptide-1 HBP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0230" }," $$" :[{" #name" :" text" ," _" :" hexoamine biosynthesis pathway HTRA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0240" }," $$" :[{" #name" :" text" ," _" :" high temperature requirement A hAPP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0250" }," $$" :[{" #name" :" text" ," _" :" human amyloid precursor protein hPREP" },{" #name" :" keyword" ," $" :{" id" :" kwrd0260" }," $$" :[{" #name" :" text" ," _" :" human presequence protease I3A" },{" #name" :" keyword" ," $" :{" id" :" kwrd0270" }," $$" :[{" #name" :" text" ," _" :" indole-3-carboxaldehyde IRF-3" },{" #name" :" keyword" ," $" :{" id" :" kwrd0280" }," $$" :[{" #name" :" text" ," _" :" interferon regulatory factor 3 i.p." },{" #name" :" keyword" ," $" :{" id" :" kwrd0290" }," $$" :[{" #name" :" text" ," _" :" intraperitoneal LC3" },{" #name" :" keyword" 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