Alzheimer’s - Instituto Balmis de Vacunasibvacunas.com/wp-content/uploads/Alzheimer_2012.pdf · C
Transcript of Alzheimer’s - Instituto Balmis de Vacunasibvacunas.com/wp-content/uploads/Alzheimer_2012.pdf · C
Alzheimer’s Disease
Alzheimer’s Disease
Alzheimer’s Disease
Genotype
vs
Phenotype
Alzheimer’s Disease
Aging Genomics Epigenetics
Cerebrovascular disorders Metabolic disorders Environmental factors
Medicina Genómica
Ambiente
Nutrición
Etiología
Tratamiento
Diagnóstico
Genómica
Transcriptómica
Proteómica
Metabolómica
Nutrigenética
Nutrigenómica
Farmacogenética
Farmacogenómica
Quimiogenómica
Toxicogenómica
Terapia Génica
Clonación
Programa EuroEspes de Medicina Genómica
Genotipo Perfil Genómico
Fenotipo SNC
Respuesta Farmacogenómica
Etnia Historia Familiar Genotipo de Enfermedad Genotipo Farmacogenético Genotipo Farmacogenómico Genotipo Nutrigenético Genotipo Nutrigenómico
Fenotipo de Enfermedad Edad y Sexo Edad de Comienzo Estadio y Severidad Patología Concomitante Correlación Genotipo-Fenotipo Condiciones Nutricionales
Genómica Funcional Transcriptómica Proteómica Metabolómica
Intervención Terapéutica
Genotipo-Metabolismo Farmacológico Farmacocinética Farmacodinámica
Modificación Fenotípica Bioquímica Neuroquímica Neuropsicología Humor Conducta Memoria y Aprendizaje Funcionamiento Neuroimagen Función cerebral Función cerebrovascular Perfil de Expresión Génica Transcriptómica Proteómica Metabolómica
Monogenic Disorder Polygenic/Complex Disorder
Gene Gene-1 Gene-2 Gene-3 Gene-4
Mutation Genetic Variation
Abnormal Protein Abnormal Protein Network
Inheritance Pattern Inheritance Pattern Mendelian Dominant Recessive X-Linked
Non-Mendelian Complex Susceptibility
Phenotypic Expression
100% Genetic Risk in Population Phenotypic Expression
Variable Genetic Risk Associated with Environmental Factors
Family Risk Family Risk 100% Mendelian Genetics Variable Depending upon Environmental Factors
and/or Associated Medical Conditions
5-10% 80-90%
Alzheimer’s Disease
Pathogenesis
Alzheimer’s Disease Macroscopic Neuropathology
Alzheimer’s Disease Microscopic Neuropathology
APP Mutations Alzheimer’s disease
GP: N=1087 AD: N=368
Amyloid Plaque Formation in Alzheimer’s disease
Presenilin-1 (PSEN1) and 2 (PSEN2) Mutations
Presenilin-1 (PSEN1) Mutations in Alzheimer’s disease
MAPT Mutations
Alzheimer’s Disease Microscopic Neuropathology
D D
C
N APP
PEN-2
APH-1 APH-2 Nicastrin
γ-Secretase
β-Secretase
α-Secretase
Notch
C
N
GACE
TACE
C83 C99
p3 Aβ
Membrane
Cytosol
γ-Secretase Inhibitors
β-Secretase Inhibitors
α-Secretase Analogs Agonists
Internalization
Neuronal Damage
Externalization
Fibrillogenesis
Amyloid Deposition
Senile Plaques
Amyloid Angiopathy
Brain Damage
Cerebrovascular Damage
APP 21q21
PS1 14q24.3
PS2 1q31-q32
BACE 11q23.3
TACE 2p25
GACE ???
Nicastrin Chr.1
PARK1 4p21
NOTCH 19p13.2-p13.1
PEN-2 Chr.19
APH-1 Chr.1/5
APOE 19q13.2
ACE 17q23
TAU 17q21.1
CASP3 4q35
UB 17p12-p11.1
IDE 10q23-q25
A2M 12p13.3-p12.3
PSMC1 19p13.3
PSMC2 7q22.1-q22.3
HSPD1 2q33.1
LRP1 12q13.1-q13.3
PRNP 20pter-p12
CTSB 8p22
Genomic Integration
Protein Synthesis Protein Misfolding
Ubiquitin 26S Proteasome
Conformational Change
Aggregation
Protofibrils Oligomers Aggregates Chaperones
Aβ Vaccination Immunization
Aβ Aggregation Inhibitors
β-Breakers
CHO Regulators Neuroprotective Agents Antioxidants Anti-inflammatory Drugs
Gene Therapy
RNAi
Vasoactive Agents
Brain Amyloidogenesis and Potential Therapeutic Interventions
R. Cacabelos, Pharmacogenomics 2004; 5(8):1049-1105
Terapia Actual Anti-Alzheimer
EA
Galantamine
Inhibidores del Acetilcolinesterasa
Rivastigmine Tacrine Donepezil
Antagonistas de NMDA
Memantine
LTP Restauradores
Reguladores de Serotonina
Terapias en Desarrollo Clínico
Antiinflamatorios
PPR-α agonist: Roglitazone
Patología de Tau
Metabolismo de Lípidos
Estimulantes Colinérgicos
NGF
Agentes Neurotrópicos
Antioxidantes
Patología de Aβ
Antihistamínicos
Vitamin B6
Reguladores Hormonales
Enfermedad de Alzheimer
Inmunoterapia Inmunización Activa
Inmunización Pasiva
Alzheimer’s Disease
Immunotherapy
Vacuna EuroEspes EB-101
Ratón APP/PS1
Vacuna EuroEspes EB-101
Diseño Bimodal Vacuna Preventiva/Profiláctica Vacuna Terapéutica
Animales Transgénicos Doble Mutación: APP + PSEN1
Liposomas Inmunógeno/Ag: AB1-42 Factor Neurotrófico S1P (Sphingosine-1-Phosphate)
Vacuna EuroEspes EB-101
Liposomes 1,2-Dioleoyl-sn-Glycero-3-Phosphocholine (DOPC) 1-Palmitoyl-2-oeloyl-sn-glycero-3-phosphatidylglycerol, Sodium salt (POPG) Cholesterol (CHO) +/- D-Erythro-Sphingosine-1-Phosphate (S1P)
Immunogen
Amyloid-Beta 1-42
EB-101
Vacuna EuroEspes EB-101
APPswe/PS1dE9 double-transgenic mice (B6C3F1/J)
Expression of Chimeric mouse/human Amyloid Precursor Protein (Mo/HuAPP695swe) and human presenilin 1 (PS1-dE6) mutans
Preventive Protocol (pre-onset) Age: 7 weeks EB101: 9 inj 100 uL x 7 months End: 11 months
Therapeutic Protocol (post-onset) Age: 35 weeks EB101: 9 inj 100 uL x 7 months End: 18 months
Vacuna EuroEspes EB-101
Vacuna EuroEspes EB-101
Pre-Symptomatic
Onset Mild
Severe
0 5 10 15 20
Preventive Vaccination 2-11 months
Therapeutic Vaccination 10-18 months
Vacuna EuroEspes EB-101
Analytical Process Antibody titers EB-101 Prophylactic Effects EB-101 Therapeutic Effects AD Neuropathological Markers Immune Response Behavioral changes
Vacunación Preventiva Placas de β-amiloide
Vacuna
Liposomas
PBS
Vacuna EuroEspes EB-101
Vacuna
Liposomas
PBS
Ovillos neurofibrilares
Vacuna EuroEspes EB-101
Vacunación Preventiva
Vacuna Liposomas PBS
CD45 – linf B
GFAP - astroglia
CD3 – linf T
Vacuna EuroEspes EB-101
Vacunación Preventiva
Aβ/NFT
CD45/NFT
GFAP/NFT
Relación entre biomarcadores
Vacuna EuroEspes EB-101
Vacunación Preventiva
Placas de β-amiloide
PBS
Vacuna
Liposomas
Vacuna EuroEspes EB-101
Vacunación Terapéutica
Ovillos neurofibrilares
Vacuna
Liposomas
PBS
Vacuna EuroEspes EB-101
Vacunación Terapéutica
Vacuna Liposomas Control
GFAP - astroglia
CD45 – linf B
CD3 – linf T
Vacuna EuroEspes EB-101
Vacunación Terapéutica
Reducción de Proceso Amiloidogénico
Vacuna EuroEspes EB-101
Vacunación Preventiva+Terapéutica
DRUGS Metabolism Disease
PHA
RM
AC
OG
ENO
MIC
S
PHA
RM
AC
OG
ENET
ICS
Cacabelos (2005)
Genetic Polymorphisms
Pharmacokinetics Absortion Distribution Metabolism Excretion
Pharmacodynamics Receptors Ion channels Enzymes Proteins
Pathogenic mechanisms Transcriptomics Proteomics Metabolomics
Safety Efficacy
30-90% variability
Pathogenic Genes
Drug Metabolism
Drug Transporters
Pleiotropic Genes
Drug Action
Disease PGx Outcome
Phenotype-A Phenotype-B
Genotype Surrogate markers
Biomarkers
Treatment
Pathogenic genes
Pleiotropic genes
Mechanism of Action
Drug Metabolism
Drug Transporters
Transcriptomics
Proteomics
Metabolomics Disease/Phenotype Modification
Genomics
Substrates Inducers
Inhibitors
Influence of APOE genotypes on Alzheimer’s disease-related phenotypes
APOE
Beta-Amyloid Deposition
Lymphocyte Apoptosis
CSF Tau NFT
Cytokine - Histamine Levels
ApoE Levels
Arterial Atherosclerosis
Brain Function EEG/FNI
Brain Function Cognition
Senile Plaques Amyloid Angiopathy
CHO/ApoE Receptors
Cholesterol HDL/LDL/VLDL/TG
Plasma & CSF BAP
Brain Perfusion CV Hemodynamics Brain Atrophy
Liver Function GOT/GPT/GGT
Cardiovascular Function
APOE Genotype DistributionAPOE Distribution in Hypertension, Diabetes and Dementia
Cacabelos et al., EuroEspes Biomedical Research Center, 2000
Control
Hypertension
Diabetes
Dementia
0% 20% 40% 60% 80% 100%
APOE-2/2APOE-2/3APOE-2/4APOE-3/3APOE-3/4APOE-4/4
Cacabelos, Psychogeriatrics (2000)
APOE Genotypes in CNS Disorders
C ANX DEP PSY STR AD PAR ADHD MIG EPI VD VE MS CVI BT CNN MR PTBS0%
20%
40%
60%
80%
100%
APOE-2/2APOE-2/3APOE-2/4APOE-3/3APOE-3/4APOE-4/4
APOE-2/2 0,32 0 0,24 0,62 0 0 0 0 0,46 0 0 0,26 0 0 0 0 0 1,89APOE-2/3 7,3 7,72 7,64 13,58 4,48 7,79 12,33 9,52 6,91 9,86 7,07 6,05 23,81 7,97 0 8 8,7 11,86APOE-2/4 1,27 1,05 1,67 1,23 2,98 1,3 1,37 0 1,84 0 1,52 1,58 0 0,73 9,09 0 1,74 0APOE-3/3 71,11 74,74 74,22 63,58 74,63 54,55 65,75 76,19 66,82 66,2 48,99 70,79 61,9 73,19 81,82 68 64,34 67,8APOE-3/4 18,41 15,09 15,27 20,37 17,91 30,3 17,81 14,29 22,13 23,94 35,85 18,68 14,29 15,94 9,09 24 24,35 16,96APOE-4/4 1,59 1,4 0,96 0,62 0 6,06 2,74 0 1,84 0 6,57 2,64 0 2,17 0 0 0,87 1,69
p<0.
001
p<0.
001
ANX: p<0.001 v s AD, VDDEP: p<0.001 v s AD, VDPSY: p<0.005 v s AD; p<0.001 v s VD: p<0.04 v s VEAD: p<0.03 v s MIG; p<0.001 v s VE; p<0.03 v s PTBSMIG: p<0.002 v s VDVD: p<0.001 v s VE; p<0.008 v s PTBSVE: p<0.05 v s MS
C: 315ANX: 285DEP: 419PSY: 162STR: 67AD: 231PAR: 73ADHD: 42MIG: 217EPI: 71VD: 198VE: 380MS: 21CVI: 138BT: 11CNN: 25MR: 115PTBS: 59
Cacabelos et al (2010)
Control GDS-3 GDS-4 GDS-5 GDS-6 GDS-7
APOE-2/2 APOE-2/3 APOE-2/4 APOE-3/3 APOE-3/4 APOE-4/4
R. Cacabelos (2005)
Right Occipital B-DTO-Hb Variation
Time (sec/10)
0 10 20 30 40 50 60 70 80 90 100 110
Hb
(mm
ol*m
m)
-0,08
-0,06
-0,04
-0,02
0,00
DHbTHbOHb
Left Occipital S-DTO-Hb Variation
Time (sec/10)
-100 0 100 200 300 400 500 600 700
Hb
(mm
ol*m
m)
-0,2
-0,1
0,0
0,1
0,2
0,3
0,4
DHbTHbOHb
AD-APOE-3/3
Right Occipital B-DTO-Hb Variation
Time (sec/10)
0 10 20 30 40 50 60 70 80 90 100 110
Hb
(mm
ol*m
m)
-0,06
-0,05
-0,04
-0,03
-0,02
-0,01
0,00
DHbTHbOHb
Right Occipital S-DTO-Hb Variation
Time (sec/10)
-100 0 100 200 300 400 500 600 700
Hb
(mm
ol*m
m)
-0,12
-0,10
-0,08
-0,06
-0,04
-0,02
0,00
0,02
DHbTHbOHb
AD-APOE-4/4
Basal Conditions
Visual Stimulation
APOE-Related Brain Optical Topography Changes
Cacabelos et al (2008)
APOE-Related DTO-Hb Species
APOE-2/2 APOE-2/3 APOE-2/4 APOE-3/3 APOE-3/4 APOE-4/4
0
0,5
-0,5
-1
-1,5
mmol*mm BDHb SDHb BTHb STHb BOHb SOHb
1 2 3 4 5 6
7 8 9 10 11 12 13 14
(1)p<0.009 BDHb-2/3 vs BDHb-4/4(2)p<0.02 SDHb-2/3 vs SDHb-4/4(3)p<0.03 BTHb-2/3 vs BTHb-4/4(4)p<0.03 STHb-2/3 vs STHb-4/4(5)p<0.05 BOHb-2/3 vs BOHb-3/3(6)p<0.03 SOHb-2/3 vs SOHb-4/4(7)p<0.03 SDHb-3/3 vs SDHb-4/4(8)p<0.03 BTHb-3/3 vs STHb-3/3
(9)p<0.001 STHb-3/3 vs STHb-4/4(10)p<0.05 BOHb-3/3 vs SOHb-3/3(11)p<0.007 SOHb-3/3 vs SOHb-4/4(12)p<0.02 BDHb-3/4 vs BDHb-4/4(13)p<0.02 STHb-3/4 vs STHb-4/4(14)p<0.01 SOHb-3/4 vs SOHb-4/4
APOE-3/3 APOE-4/4 APOE-3/3
Basal Stimulation Recovery
APOE-2/3
APOE-2/4
APOE-3/3
APOE-3/4
APOE-4/4
Op
tica
l Bra
in T
op
ogr
aph
y
AP
OE
Ge
no
typ
e-R
ela
ted
C
ort
ical
DO
T H
em
ogl
ob
in C
on
sum
pti
on
R. Cacabelos, Expert Rev Mol Diag (2009)
R. Cacabelos, Expert Rev Mol Diag (2009)
CYP2D6-Related Therapeutic Response in Alzheimer's DiseaseCognitive Performance in Extensive (EM), Intermediate (IM),
Poor (PM) and Ultra-rapid Metabolizers (UM)
EM-0 EM-1 EM-3 EM-6 EM-9EM-12 IM-0 IM-1 IM-3 IM-6 IM-9 IM-12 PM-0 PM-1 PM-3 PM-6 PM-9PM-12UM-0 UM-1 UM-3 UM-6 UM-9UM-120
5
10
15
20
25
30
35
XSD
X 21,58 21,57 21,53 21,54 22,66 23,78 21,4 21,67 22,2 22,1 22,5 22,71 20,74 20,65 20,24 19,04 18,57 18,07 22,65 23,02 22,49 21,73 21,34 21,28SD 9,02 7,46 6,99 5,17 8,09 5,81 6,28 5,58 6,2 6,48 6,39 5,07 6,72 6,52 6,11 5,39 5,52 5,86 6,76 5,67 4,62 5,68 4,99 7,75
ExtensiveMetabolizers
IntermediateMetabolizers
PoorMetabolizers
Ultra-rapidMetabolizers
MMSE Score
Cacabelos et al (2007)
Interaction of CYP2D6 and APOE in the Pharmacogenetics of Alzheimer's DiseaseInfluence of APOE Genotypes on CYP2D6-Related Extensive (EM), Intermediate (IM) and Poor Metabolizers (PM)
10 11 13 16 19 12 20 21 23 26 29 22 30 31 33 36 39 32 40 41 43 46 49 42 50 51 53 56 59 52 70 71 73 76 79 72 80 81 83 86 89 82 90 91 93 96 99 920
10
20
30
40
MeanSD
10:*1/*1-3/3-BL11:*1/*1-3/3-1M13:*1/*1-3/3-3M16:*1/*1-3/3-6M19:*1/*1-3/3-9M12:*1/*1-3/3-12M
*1/*1-3/3
10:*1/*1-3/4-BL11:*1/*1-3/4-1M13:*1/*1-3/4-3M16:*1/*1-3/4-6M19:*1/*1-3/4-9M12:*1/*1-3/4-12M
10:*1/*1-4/4-BL11:*1/*1-4/4-1M13:*1/*1-4/4-3M16:*1/*1-4/4-6M19:*1/*1-4/4-9M12:*1/*1-4/4-12M
10:*1/*4-3/3-BL11:*1/*4-3/3-1M13:*1/*4-3/3-3M16:*1/*4-3/3-6M19:*1/*4-3/3-9M12:*1/*4-3/3-12M
10:*1/*4-3/4-BL11:*1/*4-3/4-1M13:*1/*4-3/4-3M16:*1/*4-3/4-6M19:*1/*4-3/4-9M12:*1/*4-3/4-12M
10:*4/*4-3/3-BL11:*4/*4-3/3-1M13:*4/*4-3/3-3M16:*4/*4-3/3-6M19:*4/*4-3/3-9M12:*4/*4-3/3-12M
10:*4/*4-3/4-BL11:*4/*4-3/4-1M13:*4/*4-3/4-3M16:*4/*4-3/4-6M19:*4/*4-3/4-9M12:*4/*4-3/4-12M
10:*4/*4-4/4-BL11:*4/*4-4/4-1M13:*4/*4-4/4-3M16:*4/*4-4/4-6M19:*4/*4-4/4-9M12:*4/*4-4/4-12M
*1/*1-3/4 *1/*1-4/4 *1/*4-3/3 *1/*4-3/4 *4/*4-3/3 *4/*4-3/4 *4/*4-4/4
Extensiv e Metabolizers Intermediate Metabolizers Poor Metabolizers
MMSE Scor (mean)
Cacabelos (2007)
Farmacogenómica
Fármacos a la Carta
Food Drug
Nutrigenomics Pharmacogenomics
Outcome
Efficacy Safety
Personalized Nutrition
Personalized Therapeutics
Immunotherapy
World Guide for Drug Use and Pharmacogenomics