new gene and new target in alzheimer disease

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new gene and new target in alzheimer disease

  1. 1. Review Article Continuum 2013;19(2):358–371 New Genes and New Insights from Old Genes: Update on Alzheimer Disease John M. Ringman, MD, MS; Giovanni Coppola, MD Dr Suredra Khosya D.M. Student IHBAS
  2. 2. INTRODUCTION Alzheimer disease (AD) is most common cause of dementia This review Understanding of the genetic underpinnings of AD Clinical relevance where applicable How guiding future research into treatments and prevention of AD
  3. 3. Alzheimer's disease first described by Alois Alzheimer in 1907 AD divided into 2 subtypes : early-onset AD (EOAD) and late-onset AD (LOAD). EOAD accounts 1% to 6% of all cases ranges from 30 to 60 or 65yr LOAD most common form of AD, an age onset later than 60 or 65yr Both EOAD and LOAD may occur in people with a positive family history of AD. 60% of EOAD have multiple cases of AD within family,13% inherited in an autosomal dominant manner with at least 3 generations affected AD is a complex disorder that is likely to involve multiple susceptibility genes and environmental factors
  4. 4. Amyloid Precursor Protein Mutations in the APP gene first mutations in familial AD N-terminal (the ᵦ-secretase cleavage site) and C-terminal (the γ- secretase cleavage site) ends of the Aᵦ portion of APP, and affect the amount of Aᵦ produced by cells The V717I substitution in APP, occurring near the γ-secretase site, was the first described familial AD Mutation Duplications of the APP in familial AD associated with cerebral Amyloid angiopathy (CAA) Variant near the ᵦ-secretase cleavage site (A673T) in APP associated with decreased production of Aᵦ and decreased risk for late- onset
  5. 5. Aβ42 peptides form soluble oligomers of ~4 to 40 peptides. These oligomers interact with other proteins and precipitate to form amyloid plaques. Soluble oligomers of Aβ42 (containing ~12 to 40 peptides) are toxic to neurons. Because of its higher rate of fibrillization and insolubility, Aβ42 is more abundant than Aβ40 within the plaques. 10 Soluble Oligomers of Aβ42
  6. 6. Normal function of presenilin’s g-secretase activity: Notch signaling? APP cleavage would be a “side effect” Components of the core γ-secretase proteolytic complex: Presinilin (either PS1 or PS2), anterior pharynx-defective 1 (APH-1), nicastrin (NCT), and presenilin enhancer 2 (PEN-2).. Barthet et al, Progress in Neurobiology 2012 11
  7. 7. Red circles: presenilin 1 and APP mutations associated with familial AD Hardy and Selkoe, 2002, Science presenilin 1 is part of -secretase, a membrane-associated protease 12
  8. 8. Presenilin 1 PSEN1 mutations are the most common cause of familial AD The Presenilin 1 protein (PS1) catalytic site of the γ-secretase complex in APP protein to produce Aᵦ fragments PSEN1 mutations lead increased absolute or relative production of Aᵦ42 PSEN1 mutations cause the youngest age of symptom onset (44-46yrs) PSEN1 have atypical features including spastic paraparesis, early myoclonus, and seizures.
  9. 9. PSEN1 tended to be younger (42 versus 56 years of age at onset) More likely memory complaints as the presenting feature (84% versus 58% ,nonfamilial frequently presenting with visuospatial and language deficits) More likely have significant headaches, myoclonus, gait abnormalities, and pseudobulbar affect The presence of such features in a young-onset case of AD when the family history is unavailable clinician to consider genetic testing
  10. 10. Presenilin 2 PSEN2 gene are rarest and have the oldest and most variable age of onset PSEN2 have mean age of onset of 54 years range from 39 to 75yr People with the N141I mutation, seizures were present in 31% Because the pathogenicity of variants in PSEN2 is not always clear Caution needs to be interpreting results of such testing with patients and their families
  11. 11. APOLIPOPROTEIN-E ApoE involved in lipid transport that acts as a scaffold in HDL Highly expressed in the liver and in the CNS Addition to transporting lipids, it also has a role in the transportation Of forms of Aᵦ including A ᵦ42 ApoE (APOE) is highly polymorphic; the APOE*E3 allele is the most common, followed by the *E4 allele, which is in turn more common than the *E2 allele. *E4 conferring a greater risk than *E3, which in turn confers a Higher risk than the *E2 allele
  12. 12. Multiple ways of influencing the Aᵦ clearance through the ApoE pathway have been suggested like ApoE mimetic ↑ Production with peroxisome proliferator-activated receptorgamma (PPARγ) agonists and the liver X receptor (LXR) agonist bexarotene Prevalence of the *E4 allele in the population typically in the range of 15% to 20%, Among people with AD, the prevalence is around 50% Having two copies of APOE*E4 increases the risk of a younger age of AD onset and makes the development of AD by age 80 highly probable Polymorphism within the neighboring TOMM40 gene explains part of the risk traditionally attributed to the APOE locus
  13. 13. OTHER RISK FACTORS FOR ALZHEIMER DISEASE Common Variants
  14. 14. Clusterin (CLU), phosphatidylinositol binding clathrin assembly protein (PICALM), and complement receptor type 1 (CR1) Bridging integrator protein-1 (BIN1) ABC transporter member 7 (ABCA7) membrane-spanning 4-domains, subfamily A, member 4(MS4A4A)/ membrane-spanning 4-domains, subfamily A, member 4E (MS4A4E)/membrane-spanning 4-domains, subfamily A, member 6A (MS4A6A) Ephrin receptor ephA1 (EPHA1), CD33 antigen (CD33), and CD2- associated protein (CD2AP)
  15. 15. Like ApoE, Clu involved in lipid transport in both the periphery and the brain Clu also is hypothesized to act as an extracellular chaperone that influences Aβ-aggregation and receptor-mediated Aβ clearance by endocytosis Unlike APOE, there are no known coding variants that account for the observed genetic association, suggesting that genetic variation in expression levels may be responsible for altered risk for AD Clusterin (CLU)
  16. 16. phosphatidylinositol binding clathrin assembly protein (PICALM),complement receptor type 1 (CR1) PICAM encodes a clathrin assembly protein The protein is involved in AP2-dependent clathrin-mediated endocytosis at the neuromuscular junction The polymorphisms of this gene are associated with the risk of Alzheimer disease. Complement component (3b/4b) receptor 1 (CR1), the main receptor of complement C3b protein, binds Aβ and thus may promote clearance
  17. 17. SORL1 encodes a protein SorLA Important in intracellular APP trafficking When cell-surface APP is re-cycled via the endocytic pathway SorLA directs APP to processing by presenilins to produce Aβ Another function of SorLA related to AD is as a lipoprotein receptor that can bind Apo E Clu, also known as apolipoprotein J (ApoJ) SORL1
  18. 18. ABCA7 encodes protein belonging to ABC superfamily of transporters. Function in the efflux of phospholipids and possibly cholesterol ABCA7 levels are regulated by sterol-responsive/regulatory element binding protein in response to cholesterol levels While ABCA7 is clearly involved in lipid metabolism, how this protein is connected to AD will require additional work ABCA7
  19. 19. Guidelines for Genetic Testing in Alzheimer Disease 1. A comprehensive family history should be obtained to reveal the likelihood, considering causes of death, of a family history of AD or other causes of dementia 2. Patients should be fully informed regarding the limits of the understanding of the genetics of AD and of the ability to treat or prevent it 3. Testing for AD in the pediatric population is not recommended 4. Testing for risk-susceptibility genes such as APOE is not widely recommended except in the context of fully informed patients and families, as in research studies.
  20. 20. Regard testing for APP, PSEN1, or PSEN2 in symptomatic patients Testing should be offered in the context of a family history of autosomal dominant inheritance in which one or more cases are of early onset, or in young-onset cases with unknown family history Regarding the implications for asymptomatic people 1.Asymptomatic first-degree relatives have 50% likelihood of inheriting the mutation and disease in the case of a pathogenic mutation being identified in an affected patient 2.Testing for asymptomatic at-risk subjects should be performed in accordance with the International Huntington Association and World Federation of Neurology Research Group on Huntington’s Chorea Guidelines 3. People thought to be asymptomatic should undergo cognitive and psychological evaluations to better define their status and ability to comprehend and cope with results.
  21. 21. SUMMARY In the last 30 years there have been substantial advances in understanding of the genetic basis of AD, although genetic assessment is currently of limited utility in clinical practice because of the low frequency (Mendelian mutations) or small effect size (common risk factors) of the currently known susceptibility genes. However, genetic studies are identifying with confidence a number of novel risk genes that will improve understanding of disease biology and possibly the identification of therapeutic targets.
  22. 22. APRAHAMIAN et al: NEW TREATMENTS FOR AD 451 Natural history of AD with treatment possibilities.
  23. 23. APRAHAMIAN et al: NEW TREATMENTS FOR AD 453
  24. 24. Compound Target/treatment Current phase ANI 1792 21-23 CAD10624 bapineuzumab Solanezumab23 25 Vaccine - active immunization Vaccine - active immunization beta-amyloid monoclonal antibody beta-amyloid monoclonal antibody Interrupted at phase I (severe side effects as meningoencephalitis) Phase I (ongoing) Phase III (ongoing) Phase III (ongoing) Ponezumab 26 Gantenerzumab Crenezumab27 Semagacestat26 27 beta-amyloid monoclonal antibody beta-amyloid monoclonal antibody beta-amyloid monoclonal antibody Gamma-secretase inhibitor Interrupted at phase II (no efficacy) Phase I (ongoing) Phase I (ongoing) Interrupted at phase III (no efficacy and risk for skin cancer) Avagacestat 28 GRL-83429 TAK-07030 Gamma-secretase inhibitor beta-secretase inhibitor beta-secretase inhibitor Phase II (ongoing) Ongoing Ongoing CHF5074 31 DAPT31 Curcumin22 Nonsteroid antinflammatory agent Prototypal gamma-secretase inhibitor Anti-amyloid aggregator Ongoing Ongoing Ongoing DAPT, [N-(3, 5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester Compounds targeted to anti-beta-amyloid treatment
  25. 25. Neurotransmitter-based Acetylcholine Serotonin Norepinephrine/Dopamine GAbA Glutamate Glycine Glial modulating drugs Direct glial target RAGE receptor antagonists TNF alpha antagonists Neuroprotection Antioxidants Miscellaneous Anti-tau or tau modulators Microtubule stabilizers Kinase inhibitors (GSK-3,GSK-3,CDK5) Miscellaneous Agents under research ST 101, AF 267b, AbT 089, AZD 3480, MEM 3454, EVP-6124, Posiphen, Huperzine 5-HT4 partial agonists, 5-HT1A agonists/antagonists, 5-HT6 antagonists MAO A and MAO b inhibitors GAbAb antagonists AMPA potentiators Partial agonists G and GM CSF, Nitroflurbiprofen, ONO-2506, Tacrolimus TTP 488 Enbrel Vitamin C and E, alpha lipoic acid, CoQ10 Phosphodiesterase inhibitors, PPARagonistsandinsulin,SIRT1activators, Growth factors (bDNF and NGF), Dimebon NAP (AL-108) and Methylene blue (Rember) Lithium, AZD-1080, minocycline Phosphodiesterase-4 inhibitors, immunotherapies GAbA, gamma-aminobutyric acid; RAGE, receptor for advanced glycation endproducts; TNF, tumor necrosis factor; GSK, glycogen synthase kinase; CDK, cyclin-dependent kinase; 5-HT (4, 1A and 6), 5-hydroxytryptamine (receptor subtypes); MAO (A and B), monoamine oxidase (A and B subtypes); AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionicacidreceptor;PPAR,peroxisome proliferator-activated receptors; SIRT1, sirtuin (silent mating type information regulation 2 homolog)-1; bDNF, brain- derived neurotrophic fator; NGF, nerve growth factor; NAP, neuronal microtubule-interacting agent (a peptide of eight amino acids, NAPVSIPQ) treatments other than anti-amyloid therapy under research for Alzheimer's disease1
  26. 26. Gene name Gene symbol Inheritance Location Onset range Amyloid precursor protein APP autosomal dominant 21q21.3 38–69 Presenilin 1 PSEN1 autosomal dominant 14q24.2 25–65 Presenilin 2 PSEN2 autosomal dominant, reduced penetrance lq42.13 41–88 Autosomal Dominant AD genes
  27. 27. Gene Chr.: Mb Top SNPs P, ORs (C.I.) APOE 19:45.4 rs4420638 a , b ; rs7412 & rs429358 c ; rs2075650b b , d 1.1 × 10 −266 , 3.84(3.56–4.14) a 1.04 × 10 −295 , 2.53 (2.41–2.66) d CLU 8:27.5 rsl532278 a ; rs11136000 d 8.3 × 10 −8 , 0.89 (0.85–0.93) a 1.62 × 10 −16 , 0.85 (0.82–0.88) d CR1 1:207.8 rs6701713 a rs6656401 e 4.6 × 10 −10 , 1.16(1.11–1.22) a 3.5 × 10 −9 , 1.21(1.14–1.29) PICALM 11:85.8 rs561655 a rs3851179 d 7.0 × l0 −11 , 0.87 (0.84–0.91) 3 3.16 × 10 −12 , 0.87 (0.84–0.91) d BIN1 2:127.9 rs7561528 a rs744373 d 4.2 × 10 −14 , 1.17 (1.13–1.22) 3 3.16 × 10 −12 , 0.87 (0.84–0.91) d CD33 19:51.7 rs3865444 a 1.6 × 10 −9 ,0.91 (0.88–0.93) a , f , g ABCA7 19:1.1 rs3752246 a rs3764650 e 5.8 × 10 −7 , 1.15 (1.09–1.21) 3 5.0 × 10 −21 , 1.23(1.17–1.28) f , g EPHA1 7:143.1 Rs11767557 a 6.0 × 10 −10 , 0.90 (0.86–0.93) a , f , g CD2AP 6:47.5 rs9349407 a 8.6 × 10 −9 , 1.11 (1.07–1.15) a , f , g MS4A4A/ MS4A6A/ MS4A4E 11:60.0 rs4938933 a rs610932 e rs670139 e 8.2 × 10 −12 , 0.89 (0.87–0.92) 3 1.2 × 10 −16 , 0.91 (0.88–0.93) f , g 1.1 × 10 −10 , 1.08 (1.06–1.11) f , g SORL1 11:121.3 rs668387 h rs3781835 a 0.001, 1.08 (1.03–1.13) h 2.9 × 10 −4 , 0.72 (0.60–0.86) a AD susceptibility genes
  28. 28. First, APP, PSEN1, and PSEN2 genes as autosomal dominant causes of AD with early-onset AD Second the late-onset AD risk loci are replicable across independent data sets using cohorts ascertained by a variety of approaches and cases diagnosed in numerous research centers. Third APOE is by far the largest effect loci for late-onset AD. A better estimate of effect size comes from studies where the SNPs responsible for the ε2/ε3/ε4 alleles are directly genotyped and different genotypes considered separately Fourth small effect risk loci will be identified for late-onset AD, This will require larger sample sizes. To achieve this, an international effort called the International Genomics Alzheimer’s Project (IGAP) is underway with participation of the ADGC, CHARGE, GERAD, and EADI consortia
  29. 29. 41
  30. 30. Pathogenic hypotheses for mostly synaptic toxicity in Alzheimer’s disease Loss of synapses correlates better than plaques or tangles with cognitive deficits 42

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