Date post: | 21-Mar-2018 |
Category: |
Documents |
Upload: | doankhuong |
View: | 214 times |
Download: | 2 times |
Therapeutic Target for Alzheimer’s Disease
Tapan Audhya, PhD. New York University, NY, USA
Health Diagnostics & Research Institute, NJ, [email protected]
First International Congress on Updates and Advances in the field of
Clinical Nutrition and Orthomolecular Medicine2011, Valencia, Spain
Types of Alzheimer Disease (AD)
1.Familial Alzheimer Disease (FAD)
2.Early-onset Familial Alzheimer Disease (EOFAD)
3.Late-onset Alzheimer Disease (LOAD)
(sporadic Alzheimer Disease)
Cont….
FAD:a) Entirely inheritedb) Affected family members of at least two
generationc) Often starts at age 40’sd) Extremely rare 1-2% of total
Cont…
EOFAD: a) Autosomal Dominant Mutationb) Usually close to 160 mutation in chromosomes -1,
-14, -21, and 19 (APO€4)c) Virus infection in young aged) Increase in Aβ production e) Symptoms of disease appear before the age of 65 f) Approximately 10-20% of total AD are affectedg) Easily identified from muscle twitching and spasm
(myoclonus)h) Chronic Inflammation
Cont..LOAD:
a) Most common form, accounting for about 80%b) Usually show symptoms after age 65 and half of them
over 85c) May or may not be hereditaryd) Several polymorphic gene in this group has been
identified in chromosome-10 and 6e) Common symptoms are : Depression, CFS/ME, high
oxidative stress, defects in glucose and lipid metabolism, high Cortisol & glutamic acid.
f) Produce Aβ peptides and there is imbalance between Aβ production and clearance
g) Lack of B-vitamin, ω3 fatty acid & antioxidants. Low level of acetylcholine and high level of toxic chemical.
Level of Hormones in HPA-axis of AD
28 - 646 – 45β-Endorphin(pg/ml)
40 - 16014 - 90ACTH (pg/ml)
8 - 282 - 12CRF (pg/ml)
21 -333 - 16Cortisol (4 PM) (µg/dl)
30 - 5410 - 25Cortisol (8 AM)(µg/dl)
LOAD (n=88)Normal (n=67)
Test for Oxidative Stress of AD
0.09 ± 0.10.15 ± 0.05BH4/BH2
3.2 ± 0.265.3 ± 0.47SAM/SAH
9.6 ± 1.013.8 ± 1.2GSH/GSSG
1.6 ± 0.110.58 ± 0.068-OH-2dG (PL)(ng/ml)
9.8 ± 1.12.9 ± 0.32Nitrotyrosine (PL)(ng/ml)
LOADNormal
Antioxidant Enzymes in AD
18.4 ± 1.211.5 ± 1.4Super-oxide Dismutase(units/min/mg Hb)
8.2 ± 1.16.8 ± 0.85
190.6 ± 12.8165 ± 10.6Catalase(units/min/mg Hb)
AD(N=42)
Normal(N=140)Glutathione Peroxidase
(µmole/NADPH/min/mg Hb)
Test for Depression of AD
3.2 ± 0.55.4 ± 0.76Nor-epinephrine
(Platelet)(ng/109 cells)
89 ± 7.7108 ± 12.2
(M) 175 ± 15.3(F) 245 ± 25.8
Serotonin (Platelet)(ng/109 cells)
LOADNormal
Test for Methylation Block of AD
83.4 ± 7.7138 ± 11CH3-cobalamine(PL)(pmole/L)
206 ± 18550 ± 37Folic acid (RBC)(nmole/L)
6.3 ± 0.147.9 ± 0.83Folic acid (PL)(nmole/L)
LOADNormal
(B12)
Km for CH2-THF is 88.0 umole/L
{5,10,Methylene THF
5-CH3-THF dUMP
THF
MTHFR (FAD)(Reduction) (1)
Ser
dTMP
DNA synth. Repair
10 Formyl THF
5 Formyl THF
5, 10, Methenyl THF
(2)(oxidation)
Diet
Methionine
SAM
SAH
Adenosine
Meth.Synthase
HS
SerineB 6
Cystathionine
a-keto + CysteineButyrate
Succinate
Glutathione
TCACycle
HS
DNA and ProteinMethylation
Methionine is in fasting conditionHS Cysteine is after dinner (meal) conditon
MTHFR Needs FAD. It is a dimer of 77k DA; each non covalently bound to FADRequire NADH for reduction.Km for NADPH is 16 umole/L
B12
and Km for CH2-THF is 88.0 μmole/L
Folate Metabolism: Alternate Pathways
Inosine
Uric acidB6
CBS
ATP
(methyltrap) Ring
Closure
Formyl transfercoenzyme
NADPH
Glycine +P-5-P+ serine-oH-methylase
ATP + HC00H+FH4Methyl
transferase
(FH4)
MSB12
Healthy Neuron Vs. Dying Neuron in Alzheimer
Pathological Features
Schematic Diagrams of the β-amyloid Precursor Protein (APP) and its Metabolic Derivatives
Measurement of β-amyloid (Aβ) Peptide• Aβ1- 42 Found in Neurotics plaques
It is hydrophobic and prone to aggregation• Aβ1- 40 More abundant than Aβ1- 42
• Both of these peptides and their auto-antibodies are found in CSF and plasma of normal, mild cognitive impaired (MCI), AD patients and their extended families.
• Beside brain, the peptides are present in various human tissues, such as, platelets, liver, skeletal muscles, kidney, lungs, skin, intestine and sc. tissue in ratio 90/10
• A transporter dependent movement is involved in transporting Aβ from CSF to plasma via interstitial fluid (ISF). Two such transporters are LRP-1* and RAGE*. Insulin helps the clearance of Aβ peptide from the brain.
LPR-1 – Low density lipoprotein receptor-related protein-1RAGE – Receptor for advanced glycation end products
Effect of Dissociation of Plasma Amyloid Protein
0
0.2
0.4
0.6
0.8
1
1.2
Control (N=35) AD (N= 23)
ControlAD
Effect of Dissociation of Plasma Amyloid Protein
Control (N = 35) AD (N = 25)
Before
After Before
After
Level of Plasma Aβ(1- 40) and Aβ(1- 42) of Geriatric Population with LOAD
20.6 – 30.8538 - 726
26.1 – 47.6240 – 407
30.3 – 51.6218 – 245
17.8 – 40.0187 – 212
14.2 – 21.6159 – 178
5.6 – 10.168 - 138
Pg/mlPg/ml
15.9 – 19.0177.6 – 200.23786 – 90
16.2 – 18.3167.2 – 180.64681 – 85
19.7 – 30.7153.4 – 177.94976 – 80
11.6 – 21.5130.2 – 166.66271 – 75
9.6 – 15.9110.6 – 135.62566 - 70
2.2 – 6.750.2 – 100.73160 - 65
Aβ(1- 42)Aβ(1- 40)NAge
Level of CSF Aβ(1- 40) and Aβ(1- 42) in Populationwith Different ADAS-cog Score
(ng/ml)(ng/ml)
Aβ(1- 40)
14.615.34237-52Severe
6.413.64530-35Moderate
18.114.24716 -28Mild
7.420.63910 -20Questionable
3.216.4410 -5Normal
Aβ(1- 42)NADAS-cogScore
Level of Plasma Aβ(1- 40) and Aβ(1- 42) &ADAS-cog Score
157.4 – 198.8643 – 128437-52Severe
187.6 – 251.3503 – 72130-35Moderate
142.7 – 192.3309 – 516 11-28Mild
54.6 – 81.4230-26810-20Questionable
8.2 – 15.7142-1590-5Normal
Aβ(1- 42)pg/ml
Aβ(1- 40)pg/ml
ADAS-cog Score
Level of Aβ Peptides in the Tissue of Frontal Cortex in AD Patient
1913 ± 1341521 ± 32911Late Onset AD(ADAS-cog > 28
2748 ± 1311931 ± 40610
(pmole/g tissue)(pmole/g tissue)Early Onset FAD(ADAS-cog > 28)
A β (1- 42)A β (1- 40)NDementia Type
Dissociated Antibody Conc. Vs. Age
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Control (N=35)60 70 80
AGE ( CONTROL)
N =25
N=21
N=18
Dissociated Antibody Conc. Vs. Age
0
0.2
0.4
0.6
0.8
1
1.2
AD (N=47)
60
70
80
90
AD
N=21
N=27
N=27N=15
4343
107107
5353
4444
6969NN
Cognitive Cognitive
Vit. K Vit. K
Cognitive Cognitive NMDA NMDA receptor receptor antagonist, antagonist, glutamate glutamate
Cognitive Cognitive
DepressionDepression
4.24.29090Vit Vit –– EE(natural)(natural)
25 Iu25 Iu/kg /kg BWBW
43.043.05656Huperzine Huperzine -- AA(200 (200 µµgg/day)/day)
30.130.19090PSPS1.0g /day1.0g /day
39.039.0168168PCPC1.4g/day1.4g/day
26.126.19090ArginineArginine1.5 g/day1.5 g/day
%%RespondersResponders
TreatmentTreatmentPeriod (days)Period (days)AgentsAgents
9696
6464
129129
9494
7171
6262NN
Energy Energy Nor epi Nor epi DopamineDopamine
Memory Memory Bl. Viscosity Bl. Viscosity
CognitiveCognitiveDepression Depression Blood Blood viscosityviscosity
%%RespondersResponders
TreatmentTreatmentPeriod (days)Period (days)AgentsAgents
46.046.06060CDPCDP--cholinecholine(1gm/day)(1gm/day)
20.020.06060VinpocetineVinpocetine(25 mg/day)(25 mg/day)
67.467.49090ωω33 Fatty acidFatty acid(2 g/day)(2 g/day)
32.032.03030Ginko biloba (761)Ginko biloba (761)160 mg/day160 mg/day
36.036.0365365Folic acidFolic acid600 600 µµg/dayg/day
44.044.090 90 Methyl CobalamineMethyl Cobalamine1 mg/day S.C1 mg/day S.C
Ginkgo Biloba Extract(EGb – 761)
Flavonoids (24%)
┼
Terpenoid (6%)
┼
Isorhamnetin glycosideKaempferolQuercetin
Ginkgolides A, B, C
Depression Depression Cognitive Cognitive
%%ResponderResponder
ss
TreatmentTreatmentPeriod (days)Period (days)NNAgentsAgents
16.316.31811817676VitaminVitamin--AA600 Iu/kg600 Iu/kg
16.416.440404747HBOTHBOT1.3/40/24%1.3/40/24%
63.463.4365365132132LithiumLithium150 mg/day150 mg/day
16.816.83653654747LL--carnitinecarnitine1.0 gm/day1.0 gm/day
18.418.48484121121NN--acetyl Cysteineacetyl Cysteine1.5 g/day1.5 g/day
Structure of (A) Curcumin (B) demethoxycurcumin and(C) bisdemethoxycurcumin
Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-cog) 11-item
Memory and new learning 0 – 35Word recall 0 – 10
(mean number of words not recalled)Orientation 0 - 8(one point for each incorrect response)Word Recognition 0 – 12(mean number of incorrect responses)Remembering test Instructions 0 – 5Language 0 - 25
Commands 0 - 5 Spoken language ability 0 – 5Naming objects/fingers 0 – 5 Word-finding difficulty 0 – 5 Comprehension 0 – 5
Praxis 0 - 10Constructional praxis 0 – 5Ideational praxis 0 – 5
Total 0 - 70Increasing scores indicate worsening cognitive function
Score Range
Change on ADAS-cog Sub-items at Wk 26
0.012*0.4210.032*
0.013*0.1060.060
< 0.001*0.037*0.0950.023*0.014*
pvalue†
Placebo (N = 159)
Mean ± SDCurcuminoids
N= 290)
142142142
141137143134142135141139N
259258259
256249259245258249258255N
–0.2 ± 1.00.0 ± 1.0
–0.3 ± 1.0
–0.1 ± 1.2–0.2 ± 3.6–0.1 ± 1.7–0.1 ± 1.3–0.1 ± 0.9–0.1 ± 1.1
0.0 ± 1.30.1 ± 1.3
Change atWk 26
Item 11: comprehensionItem 10: word finding difficultyItem 9: spoken language ability
Item 8: remembering test instructions
Item 7: word recognitionItem 6: orientationItem 5: ideational praxisItem 4: naming objects/fingersItem 3: constructional praxisItem 2: commandsItem 1: word recallADAS-cog sub-item
0.2 ± 1.00.1 ± 1.00.1 ± 1.2
0.2 ± 1.30.5 ± 3.30.4 ± 1.80.4 ± 1.50.1 ± 0.80.2 ± 1.00.6 ± 1.21.0 ± 1.3
Change atWk 26
*p < 0.05† p value based on van Elteren test
Treatment Difference at Wk 26 on ADAS-cog by States
Illinois (N = 19)S. Dakota (N = 21)Wisconsin (N = 41)New Jersey (N = 63)New York (N = 59)Texas (N = 63)California (N = 48)Arizona (N = 118)Florida (N = 18)N. Dakota (N = 17)Montana (N = 19)Iowa (N = 45)
–10 0 10 20
LS mean difference (95% CI).
–20
–39.67
–29.92
46.92
Favor CurcuminoidsFavor placebo
Placebo Controlled Supplement StudyPlacebo Controlled Supplement Study
# of Volunteers = 476 (309 M + 167 F)# of Volunteers = 476 (309 M + 167 F)
6 Month 6 Month
208(134M + 74 F)
RespondersResponders
1. Howthorne Effect 2. Placebo Effect & Drift
6 Month
238(154M + 84 F)
6 Month6 Month
Responders
6 Month
Responders
6 Month6 Month
Responders
6 Month
238(155M + 83 F)
6 Month
Responders
6 Month
Responders
36 (18%)(31M + 5F)
6 Months
Responders
172 (76%)(93M + 79 F)
226(143M + 83 F)
6 Months
Curcuminoids – 2 gm/day + Vitamin D3 2000 iu/day
Possible Bioactivity of Curcuminoids
• D3 interacts & Curcuminoids to stimulate Aβ peptide clearance via macrophage (Type I- II)
• Curcuminoids enhanced memory in Aβamyloid infused rat model of AD
• It inhibits acetylcholine esterase and stimulate creatine kinase in vitro and invivo in rat model.
• Curcuminoids and vit. E mixture control inflammation of brain by modulating Aβinduced toxicity.
Acetylcholinesterase (mU/ml) Acetylcholine (nM)
Assay of Ach & Ach-esterase