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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Metabolic dysfunction, aging and cognition
Norman J. HaugheyJohns Hopkins University School of Medicine
The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
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Trends in Neurosciences 2015 38, 36-44DOI: (10.1016/j.tins.2014.10.002)
Copyright © 2014 Elsevier Ltd Terms and Conditions
Metabolic
Aging
Metabolic age is a
comparison between
a person's basal
metabolic rate (BMR)
against the average
BMR for that persons
age
Calculate your BMR (basal metabolic rate): Women: BMR = 655 + ( 4.35 x weight in pounds ) + ( 4.7 x height in inches ) - ( 4.7 x age in years ) Men: BMR = 66 + ( 6.23 x weight in pounds ) + ( 12.7 x height in inches ) - ( 6.8 x age in years )
http://www.elsevier.com/termsandconditionshttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282817/figure/F1/
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Metabolic rate decreases and percentage of fat increases with age
https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwic7I2t47DdAhVyU98KHcjNAR8QjRx6BAgBEAU&url=https://healthjade.com/can-i-boost-my-metabolism-to-lose-weight/&psig=AOvVaw1ordH_UgJpE0LPxnp3ltu3&ust=1536680557937077https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwjUlfXX47DdAhXndN8KHTfUDtkQjRx6BAgBEAU&url=http://www.ucl.ac.uk/~ucbcdab/enbalance/definitions.htm&psig=AOvVaw1ordH_UgJpE0LPxnp3ltu3&ust=1536680557937077
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Insulin Resistance and Metabolic SyndromeIn non-diabetic individuals, insulin
resistance commonly clusters with:
•upper body fat distribution
•glucose intolerance
•relative hypertension
•dyslipidemia
•age
•sex
•ethnicity
•sub-clinical inflammation
•circulating adipokines
•intracellular lipid accumulation in liver
and skeletal muscle
•Strong association with Alzheimer’s
disease
•Growing association with CI in HIV
https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwiCrsTAsrPdAhVHh-AKHRvuCTkQjRx6BAgBEAU&url=https://www.thelancet.com/journals/landia/article/PIIS2213-8587(13)70062-7/fulltext&psig=AOvVaw2rcd-n9zTQHHTatgXrPrcs&ust=1536770244451586
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Human studies showing metabolic changes with HIV
Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients. AIDS 2015Alex M. Dickens; Daniel C. Anthony; Reena Deutsch; Michelle M. Mielke; Timothy D.W. Claridge; Igor Grant; Donald Franklin; Debra Rosario; Thomas Marcotte; Scott Letendre; Justin C. McArthur; Norman J. Haughey
Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection. Neurology 2014Andrew C. Young, Constantin T. Yiannoutsos, PhD, Manu Hegde, MD, PhD, Evelyn Lee, Julia Peterson, Rudy Walter, Richard W. Price, MD, Dieter J. Meyerhoff, PhD and Serena Spudich, MD
Role of obesity, metabolic variables, and diabetes in HIV-associated neurocognitive disorder. Neurology 2012McCutchan JA1, Marquie-Beck JA, Fitzsimons CA, Letendre SL, Ellis RJ, Heaton RK, Wolfson T, Rosario D, Alexander TJ, Marra C, Ances BM, Grant I; CHARTER Group.
Abdominal obesity contributes to neurocognitive impairment in HIV-infected patients with increased inflammation and immune activation. JAIDS 2015Sattler FR1, He J, Letendre S, Wilson C, Sanders C, Heaton R, Ellis R, Franklin D, Aldrovandi G, MarraCM, Clifford D, Morgello S, Grant I, McCutchan JA; CHARTER Group.
Complement Component 3 Is Associated with Metabolic Comorbidities in Older HIV-Positive Adults. AIDS Res 2016Bryant AK1, Fazeli PL2, Letendre SL1, Ellis RJ1,3, Potter M1, Burdo TH4, Singh KK5, Jeste DV2,6, Grant I1,2, Moore DJ1,2.
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Valcour et al., JAIDS, 2006
OR = 4.33 (1.55–12.10)
Insulin resistance associated with NCI
Valcour et al., JAIDS 2006
HOMA associated with NCI in WISE
Valcour et al., AIDSrhs. 2012
BMI
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Plasma metabolic measures in the discovery cohort (CHARTER n=47)
Sta
bly Nor
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mg/d
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/HD
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cerides (
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5.5
6.0
Adip
onectin (
ug/m
L)
A B C D E
F G H I J
Kh
ud
eret
al.,
20
18 u
nd
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Sta
bly Nor
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Dec
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400In
sulin
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ol/L)
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8
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eptide (
ng/m
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r R
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C:I)
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bly Nor
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lining
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ste
rol (m
g/d
L)
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bly Nor
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L (
mg/d
L)
**
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L (
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L R
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L/H
DL R
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bly Nor
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lining
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Trigly
cerides (
mg/d
L) *
Sta
bly Nor
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Dec
lining
0
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4
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10
Adip
onectin (
ug/m
L)
A B C D E
F G H I J
Plasma metabolic measures in the validation cohort (MACS n=72)
Kh
ud
eret
al.,
20
18 u
nd
er r
evie
w
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Insulin signaling
P38 ERK
Infla
m
ma t or y cyt oki ne gene expr essi on
NFκB JNK
P P
P
P
P P P
P
P
Insulin
IRS‐p53
LRRNT
TIR
LRRN
T
LRR
NT
LRR
TLR2/4
TIR
L RR
NT
LRR
PI3K
Cdc42
Bad
mTOR
Rac‐1
Cytoskeletal rearrangement
(dendri c growth)
Apoptosis
Synapse forma on
RhoA
Akt
P P
IKKβ
TRAF6
ILR1
LPS
insulin
glucose uptake
glycolysis
glycogen synthesis
Protein synthesis
Gluco-neogenesis
Gluco-genolysis
lipolysis
ketogenesis
proteolysis
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Evidence for alterations of energy
metabolism in HIV and NC
Kosmiski et al. The Americian Journal of Clinical Nutrition; 90 (2009) 1525-1531
Symbol GeneTitle
ATP/ADP FC pvTnks TRF1-interactingADP-ribosepol 1.179 0.018Mthfd1l methylenetetrahydrofolateDH1L 1.423 0.020Arl5b ADP-ribosylationfactor-like5B 1.142 0.021Mthfd2l methylenetetrahydrofolateDH2L 1.406 0.107Atp6v1g1 ATPase,lysosomalV1subunitG1 1.195 0.128Atp1b3 ATPase,beta3polypeptide 1.215 0.473Atp5f1 ATPsynthase,mitochondrialF1c,G1 1.069 0.724Tiparp TCDD-induciblepoly(ADP-ribose)pol 1.521 0.039Abcg1 ATP-bindingcassette,sub-familyG, 1.787 0.018Atp11c ATPase,classVI,type11C 1.460 0.151Atp5s ATPsynthase,mitochondrialF0c,subs 1.168 0.056Atp11a ATPase,classVI,type11A 1.910 0.023Arf3 ADP-ribosylationfactor3 -1.505 0.031Arfrp1 ADP-ribosylationfactorrelatedp1 -1.140 0.163Atp9b ATPase,classII,type9B -1.131 0.075Arl15 ADP-ribosylationfc-like15 -1.183 0.033Atp2b4 ATPase,Ca++transporting4 -1.060 0.044Atp6v1g2 ATPase,lysosomalV1subG2 -1.812 0.007Glutamine/glutamate/glutaminase FC pvGlb1 galactosidase,beta1 1.188 0.020Got1 glutoxaloacetatetransaminase1 1.071 0.508Gclm glut-cysteineligase 1.312 0.038Gfpt1 glutaminefructose-6Ptransaminase1 1.003 0.927Qser1 glutamineandserinerich1 -1.093 0.030Tgm2 transglutaminase2 -1.054 0.419Tgm3 transglutaminase3 -1.071 0.011Tgm5 transglutaminase5 -1.091 0.142Cytochrome/mitochondria FC pvSod2 superoxidedismutase2 1.800 0.020Me2 malicenzyme2,mitochondrial 1.452 0.164Cox11 cytochromecoxidase11 -1.128 0.308Mdh2 malatedehydrogenase2,NAD 1.177 0.522Cox5a cytochromecoxidase,subunitVa -1.036 0.150Ucp2 Uncouplingprotein2 2.176 0.030Cyp46a1 cytochromeP450,f46,sfa, -2.020 0.0001Glycolysis/Glc FC pvUgcg UDP-glucoseceramide 2.232 0.007Pfkfb3 6-PF-2-kinase/fructose-2,6-biP3 1.438 0.001Pgk1 phosphoglyceratekinase1 1.337 0.336Pkm2 pyruvatekinase 1.147 0.194Ugp2 UDP-glucosepyrophosphorylase2 1.108 0.653Insulin FC pvIgfals insulin-likegrowthfactorbinding -1.162 0.058Igfbp4 insulin-likeGFbindingp4 -1.058 0.296Igfbp6 insulin-likeGFbindingp6 -1.198 0.019
HAND
• Skeletal muscle is hypermetabolic in patients with HIV
lipoatrophy.
• Possibly an adaptive thermogenesis in response to an
inability to store triglyceride fuel in a normal manner.
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism
regulating shifts in cognitive states of HIV-infected patients
Dickens AM, Anthony DC, Deutsch R, Mielke MM, Claridge TD, Grant I, Franklin D, Rosario D, Marcotte T, Letendre S, McArthur JC, Haughey NJ.
13 March 2015
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
NOSEY and 2D COSY 1H-NMR spectroscopy enabled the identification of energy metabolites
ppm12345
TSP
Lactate
Ethanol
a-glucose
anomeric
b-glucose
anomeric
LactateCitrate
Glucose resonances
Glutamine
GlutaminePyroglutamic acid
Water
Valine
Acetate
1
2
3
4
5
12345
ppm
ppm
Citrate
Lactate
b-Glucose
a-Glucose
Ethanol
Glucose
resonances
Dickens et al., AIDS; 29 (2015) 559-569
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Prognostic markers for neurocognitive decline
Predictive accuracy 86%Sensitivity 96%Specificity 76% Dickens et al., AIDS; 29 (2015) 559-569
N = 50
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Cognitive worsening: Excessive glycolysis
Adapted from: Ramsköld et al. Wikipathways
Glutamate
Glutamine
AspartateOxaloacetate
ATP
ADP
NH3 Citrate accumulates when the glycolytic rate exceeds the capacity of the TCA cycle
Citrate
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Lower cognitive reserve when aging with HIV
Chang et al., Neurobiol of Aging 2013
https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click on image to zoom&p=PMC3&id=3984923_nihms-423580-f0002.jpg
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Prognostic markers for neurocognitive improvementCurrent
CD4 Count
N = 48
Plasma viral load
Improving11(1)
≥176
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
▪ Key metabolite changes:
▪ Decreased glucose
▪ Decreased acetate
▪ Increased lactate
Cognitive improvement is associated with a shift to anaerobic glycolysis in the CNS
Glucose
Anaerobic glycolysis
Aerobic glycolysis
Pyruvate
LactateTCA cycle
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
How can we regulate CNS energy metabolism to promote anaerobic
glycolysis?
• Exercise: Kelly O’Brien, U of Toronto
Meilissa Wilson. U of Colorado
• Intranasal delivery of insulin could promote the
utilization of available glucose and the brain must
then shift to alternate energy sources
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
REFERENCE
DOSE OF
INTRANASAL
INSULIN TESTED
PATIENT
POPULATION ASSESSMENT
Benedict, 2004 160 IU (long-term) Healthy · Word list (immediate recall)
· Word list (delayed recall)
Reger, 2006 20 or 40 IU (acute) Probable AD or
MCI vs. healthy
· Story recall (immediate + delayed recall)
· Word list (immediate + delayed recall)
Benedict, 2007 20 IU Aspart* vs. 20 IURegular (long term)
Healthy men · Word list (immediate recall)
· Word list (delayed recall)
Benedict, 2008 160 IU (acute) Healthy, normal
weight, with no
medications
· Digit span (immediate recall)
· Object location (immediate recall)
· Mirror tracing (immediate recall)
Hallschmid,
2008 160 IU (long-term) Obese men · Word list (delayed recall)
· Word list (immediate recall)
Reger, 2008 20 IU (long term) AD or MCI 1. Memory score (immediate/ delayed recall ratio)
2. Voice onset time (immediate/delayed recall ratio)
Reger, 2008 10, 20, 40, 60 IU
(acute)
AD or MCI
vs. healthy
1. Story recall (immediate recall or delayed recall)
2. Word list learning (immediate recall, delayed
recall)
Krug, 2010 160 IU (acute) Healthy
postmenopausal
women
1. Digit span (immediate recall)
2. Object location(immediate recall)
Fan, 2012 I40 IU (acute) schizophrenic 1. Hopkins Verbal Learning Test
(Immediate recall)
2. Hopkins Verbal Learning Test
(Delayed )
Craft, 2012 10 or 20 IU bid AD or MCI 1. Verbal Memory Composite
Craft, 2012 20 or 40 IU AD or MCI · Story recall (delayed recall)
McIntyre, 2012 40 IU (long term) Euthymic with
bipolar disorder
· California Verbal Learning Test, second edition
· Process Dissociation Task
Burns, 2012 40 IU (acute) Early AD · fMRI activation
· Cognitive battery.
Novak , 2013 40 IU (long term) Diabetic · Brief Visuo-spatial Memory Test-
Revised
· Verbal fluency measures
Fan, 2013 40 IU (long term ) Schizophrenic · Cognitive battery.
Craft, 2013 20 IU bid AD or MCI 3. Cognitive battery.
Haley, 2013 20 IU AD 3. Cerebral glutamate concentration
4. Cognitive battery
Summary of
past and
ongoing
human
intranasal
insulin trials
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Intranasal insulin trial for NC in HIV
To examine whether intranasal insulin is
safe and well tolerated in individuals with
HAND
To examine whether intranasal insulin
improves neuroimaging markers of CNS
injury.
To examine whether intranasal insulin
improves CSF surrogate markers of
oxidative stress, axonal injury, inflammation
and abnormal amyloid metabolism.
10 subjects enrolled – 2 completed
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Intranasal insulin delivery in mice
Malhotra et. al. 2014. Methods in molecular biology
• NMR measures of energy metabolites
• RNAseq - (hippocampus)• Time course and n=3/condition
• RNAseq – neurons• RNAseq – astrocytes
• RT-PCR validation of gene expression• Energy Metabolism
• Untargeted Lipidomics• Developed method to quantitatively measure
fatty acids
• Direct measures of fatty acid oxidation
• Mitochondrial function
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Intranasal insulin mouse (hippocampus)
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0-3 -2 -1 0 1 2 3 4
6
5
4
3
2
1
0
-4 -2 0 2 4 6
Total protein-protein coding genes 21,917 genes
1 hr 6 hr
2 SD = 313 transcripts
173 transcripts up regulated
140 transcripts down regulated
2 SD = 241 transcripts
164 transcripts up regulated
77 transcripts down regulated
2 SD = 236 transcripts
181 transcripts up regulated
55 transcripts down regulated
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0-4 -2 0 2 4
15 min
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Genes that regulate -oxidationGene Name Gene
Symbol Encoded Product Function Astro
6hr Astro 12hr
Neuron 6hr
Neuron 12hr
stearoyl-CoA desaturase
SCD
Enzyme stearoyl-CoA desaturase
This gene encodes an enzyme involved in fatty acid biosynthesis, primarily oleic acid. Regulate fatty acid and cholesterol metabolism
+3 +6 +1 +2
sterol regulatory element binding transcription factor 1
Srebf1 Sterol regulatory element binding protein-1 (SREBP-1)
This gene encodes a transcription factor that binds to the sterol regulatory element-1 (SRE1).
+3 +1 -2 -1
Fatty Acid Binding Protein 3
FABP3 Protein FABP3
The intracellular fatty acid-binding proteins (FABPs) belong to a multigene family. They are thought to participate in the uptake, intracellular metabolism and or transport of long chain fatty acids
+3 +0.5 +0.5 -1
Acyl-CoA Synthetase Long-Chain Family Membrane 4
Acsl4 Long-chain fatty acid-CoA ligase 4
The protein encoded by this gene is an isozyme of the long-chain-fatty-acid-coenzyme A ligase.
+2 +0.5 +2 +0.5
protein kinase AMP-activated non-catalytic subunit beta 1
Prkab1 5’-AMP-activated protein kinase subunit beta-1
The protein encoded by this gene is a regulatory subunit of the AMP-activated protein kindase (AMPK), an important energy-sensing enzyme that monitors cellular energy status.
+2 +2 -0.5 +0.5
Ubiquinol-Cytochrome C Reductase Core Protein I
Uqcrc1 Cytochrome b-c1 complex subunit, mitochondrial
This is a component of the ubiquinol-cytochrome c reductase complex (complex II), which is part of the mitochondrial respiratory chain. This protein may mediate formation of the complex between
cytochromes c and c1
+2 +1 -1 -1
Fatty acid synthase FASN Fatty acid synthase (FAS)
The enzyme encoded by this gene catalyzes the synthesis of palmitate from acetyl-CoA and malonyl-CoA, in the presense of NADPH, into long-chain saturated fatty acids
+1 +2 +0.5 +1
Carnitine Palmitoyltransferase 1C
CPT1C Carnitine palmitoyltransferase I
The encoded protein regulates the beta-oxidation and transport of long-chain fatty acids into mitochondria
+1 +2 -1 -1
acetyl-CoA acetyltransferase 2
ACAT2 Acetyl-CoA acetyltransferase, cytosolic
The product of this gene is an enzyme involved in lipid metabolism and it encodes cytosolic acetoacetyl-CoA thiolase.
+1 +2 --- ---
Protein Kinase CAMP-Activated Catalytic Subunit
Alpha
PRKACA Catalytic subunit α of protein kinase A
This gene encodes one of the catalytic subunits of protein kinase A.
+1 +1 -0.5 -1
Protein Kinase AMP-Activated Non-Catalytic Subunit
Gamma
Prkag1 5’AMP-activated protein kinase subunit gamma-1
The protein encoded by this gene is a regulatory subunit of the AMP-activated protein kinase (AMPK).
+1 +1 -2 -2
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Validations of gene expression (Astrocytes - FA metabolic pathways)
Con
trol
1hr
6hr
12hr
0
1
2
3
4
5
FA
Synth
ase (
F.I.)
***
**
Con
trol
1hr
6hr
12hr
0
2
4
6
8
Sre
bf1
(F.I.)
******
***
Fatty Acid Uptake and Biosynthesis
Con
trol
1hr
6hr
12hr
0
1
2
3
4
UC
P3 (
F.I.)
**
**
**
Con
trol
1hr
6hr
12hr
0
1
2
3
CO
X-2
(F.I.)
**
******
Con
trol
1hr
6hr
12hr
0.0
0.5
1.0
1.5
CP
T1c (
F.I.)
*
Fatty Acid Oxidation
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
β-oxidation of fatty acids
▪ Occurs largely in peroxisomes and mitochondria
▪ Inside the cell fatty acids are elongated, desaturated and conjugated with CoA
▪ Long-chain acyl-CoAs are converted to a long-chain Acyl carnithines for transport into mitochondria
▪ Inside mitochondria Acyl carnithines are converted back into long-chain acyl-CoAs
▪ Metabolized by β-oxidation into acetyl CoA for TCA cycle
Fatty acid
Transporter
Fatty acid
Fatty acid
Fatty acyl CoA
FACS
CPT1
Acyl carnithine
CAT
Acyl carnithine
CPT2Fatty acyl CoA
Acetyl CoA
NADH/FADH2
Electron Transport Chain
ATP
β-Oxidation
TCA Cycle
Mitochondrial Matrix
Outside Cell
Inside Cell
Glycolysis – 4 ATP total (2 used)β-oxidation (palmitate) – 131 ATP (2 used)
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The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
0 1 3 6120
100
200
300
Lin
ole
ic a
cid
(1
8:2
, n
g/m
l)Time (hr)
**
*********
**
0 1 3 6120
500
1000
1500
Ole
ic a
cid
(18:1
, ng/m
l)
Time (hr)
*******
0 1 3 6120
500
1000
1500
2000
Lin
ole
nic
acid
(18:3
, ng/m
l)
Time (hr)
******
0 1 3 6120
5
10
15
20
25
Eic
osape
nta
enoic
acid
(2
0:5
, ng
/ml)
Time (hr)
***
******
***
0 1 3 6120
500
1000
1500
2000
Eic
osate
traen
oic
acid
(2
0:4
, ng/m
l)
Time (hr)
******
******
0 1 3 6120
50
100
150
200
Docosahexaenoic
acid
(2
2:6
, ng/m
l)
Time (hr)
***
***
******
***
0 1 3 6120
20
40
60
80
100
Doco
sape
nta
eno
ic a
cid
(2
2:5
, ng/m
l)
Time (hr)
********
0 1 3 6120
20
40
60
80
100
Docosate
traen
oic
acid
(2
2:4
, ng/m
l)
Time (hr)
******
*
Desaturation
18:1 18:2
0 1 3 6120
20
40
60
80
100
Dih
om
o-g
-lin
ole
nic
acid
(20:3
, ng/m
l)
Time (hr)
*
*******
0 1 3 6120
10
20
30
40
Eic
osa
die
noic
acid
(20:2
, ng/m
l)
Time (hr)
Elongation Desaturation
20:2
20:3
18:3
Desaturation
20:4 20:5 22:4
22:5 22:6
Desaturation
Desaturation Elongation Desaturation
Desaturation
Evidence for fatty acid utilization in astrocytes
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 00
5 0
1 0 0
1 5 0
2 0 0
T im e (m in )
OC
R (
pm
ol/
min
)
C o n tro l
In s u lin 3 0 '
In s u lin + F A 3 0 '* * *
* * *
F A 3 0 '
-
The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
• Metabolic abnormalities are common with HIV infection
• Contribution of HIV
• Contribution of ART
• Often are subclinical
• Promoting anerobic metabolism is neuroprotective
• Intranasal delivery of insulin shifts brain utilization to β-
oxidation of fatty acids• Produces 50X more ATP
Summary/Discussion
-
The NIMH Center for Novel Therapeutics of HIV-associated Cognitive DisordersThe NIMH Center for Novel Therapeutics of HIV-associated Cognitive Disorders
Intranasal Insulin team:Justin McArthurNorman HaugheyBarb SlusherNed SacktorSeung-Wan YooAhmet HokeNicholas MaragakisJiadi Xu (Radiology)Rexford Ahima (Division of Endocrinology,Diabetes and Metabolism)
Haughey Lab:Saja Khuder, PhD
Alex Dickens, Ph.D.
Amanda Trout
Sheng Wang, Ph.D
Erica McGrath, Ph.D.
Amrita Datta Chaudhuri, Ph.D
Seung-Wan Yoo, Ph.D
Raha Dastgheyb, Ph.D
Diana Cedillo
Ashley Middleton
Johns Hopkins Deep Sequencing
and Microarray Core FacilityConnie Talbot
Haiping Hao
Johns Hopkins ProteomicsBob Cole
Oxford
Daniel Anthony
Tim Claridge
NINDS Intramural
Avindra Nath
Joe Steiner
Carol Anderson
Muznabanu Bachani
Mayo Clinic
Michelle Mielke
UCSD
Igor Grant
Scott Letendre
Reena Deutsch
Anthony Garnst
Clint Cushman
Chris Achim
David Moore
Donald Franklin
Thomas Marcotte
With special thanks to study participants
Mt. Sinai
David Volsky
Alejandra Borjabad
Jennifer Kelschenbach
Boe-Hyun Kim
Hongxia He
Chao jiang Gu
Eran Hadas
Wei Chao
Mary Jane Potash
Susan Morgello
MACS
Joseph B. Margolick, MD
Lisa P. Jacobson
Ned Sackto
Gypsyamber D’Souza
Valentina Stosor
Jordan E. Lake
Giovanna Rappacciolo,
These studies were funded by:
NIMH Center for Novel Therapeutics: MH075673
NIMH Intranasal Insulin Therapy for HIV- Associated Neurocognitive Disorders:
P01MH105280
AG057420, DA04039, MH077542, MH075673, MH110246
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