new gene and new target in alzheimer disease
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new gene and new target in alzheimer diseaseTRANSCRIPT
Review ArticleContinuum 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
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
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
Amyloid Precursor ProteinMutations 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 theamount of Aᵦ produced by cells The V717I substitution in APP, occurring near the γ-secretase
site, wasthe first described familial AD MutationDuplications of the APP in familial AD associated with cerebralAmyloid angiopathy (CAA)Variant near the ᵦ-secretase cleavage site (A673T) in APP
associatedwith decreased production of Aᵦ and decreased risk for late-
onsetAD
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.
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Soluble Oligomers of Aβ42
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
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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
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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, earlymyoclonus, and seizures.
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
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
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
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
OTHER RISK FACTORS FOR ALZHEIMER DISEASE Common Variants
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)
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)
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
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
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
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.
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 people1.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 patient2.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 Guidelines3. People thought to be asymptomatic should undergo cognitive and psychological evaluations to better define their status and ability to comprehend and cope with results.
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.
APRAHAMIAN et al: NEW TREATMENTS FOR AD 451 Natural history of AD with treatment possibilities.
APRAHAMIAN et al: NEW TREATMENTS FOR AD 453
Compound Target/treatment Current phase
ANI 1792 21-23
CAD10624 bapineuzumab
Solanezumab23
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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
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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
DAPT 31
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
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, CDK 5)
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 agonists and insulin, SIRT1 activators, 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-isoxazolepropionic acid receptor; 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
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
Gene Chr.: Mb Top SNPs P, ORs (C.I.)APOE 19:45.4 rs4420638a,b;
rs7412 & rs429358c;rs2075650bb,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 rsl532278a;rs11136000d
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 rs6701713a
rs6656401e
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 rs561655a
rs3851179d
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 rs7561528a
rs744373d
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 rs3865444a 1.6 × 10−9,0.91 (0.88–0.93)a,f,g
ABCA7 19:1.1 rs3752246a
rs3764650e
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 Rs11767557a 6.0 × 10−10, 0.90 (0.86–0.93)a,f,g
CD2AP 6:47.5 rs9349407a 8.6 × 10−9, 1.11 (1.07–1.15)a,f,g
MS4A4A/MS4A6A/MS4A4E
11:60.0 rs4938933a
rs610932e
rs670139e
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 rs668387h
rs3781835a
0.001, 1.08 (1.03–1.13)h
2.9 × 10−4, 0.72 (0.60–0.86)a
AD susceptibility genes
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
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Pathogenic hypotheses for mostly synaptic toxicity in Alzheimer’s disease
Loss of synapses correlates better than plaques or tangles with cognitive deficits
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