Speaker:Han, Ge Date:13 May 2014 Introduction to The Alzheimer’s Disease Related Genes.
23
Speaker:Han, Ge Date:13 May 2014 Introduction to The Alzheimer’s Disease Related Genes
-
Upload
mikel-pund -
Category
Documents
-
view
228 -
download
0
Transcript of Speaker:Han, Ge Date:13 May 2014 Introduction to The Alzheimer’s Disease Related Genes.
Speaker:Han, Ge
Date:13 May 2014
Introduction to The Alzheimer’s Disease Related
Genes
2
Table of Content
§1 Introduction
§2 The Alzheimer’s Disease related genes
§3 Three FDA approved agents for Imaging of Aβ Plaques
§4 Summary
3
Discovery who: Dr.Allos Alzheimer(German psychiatrist) when:1906
Classification
Familial Alzheimer’s disease (FAD)
Sporadical Alzheimer’s disease (SAD)
Dr.Alois Alzheimer
(1864~1915)
Auguste Deter(the first person
diagnosed with AD)
http://en.wikipedia.org/wiki/Alzheimer%27s_disease
Discovery and Classification
4
Actual and estimated number of new Alzheimer disease cases in the US through the year 2050
Mount, C.Downton, C. Nat. Med. 2006, 12, 780
Growth in the number of AD
AD is estimated to have cost the world $604 billion in 2010 alone. These costs are staggering, particularly in light of predictions that the worldwide number of AD cases,
currently estimated at 36 million, will triple by 2050.
The hallmarks of AD
Alzheimer's disease brain comparison
http://en.wikipedia.org/wiki/Alzheimer%27s_disease
Amyloid plaques and neurofibrillary tangles
5
6
The Alzheimer’s Disease related genes
7
Alzheimer’s Disease is a genetically complex disease.
Familial Alzheimer’s disease related genes :APP 、 Presenilin1 and Presenilin 2...
Sporadical Alzheimer’s disease related gene :APOE4…
zh.wikipedia.org/zh-cn/
AD related genes
Henry W. Querfurth, Frank M. LaFerla, N. Engl .J .Med. 2010; 362:329-344
Two pathways exist for the processing of APP, one being nonamyloidogenic whilst the other pathway is amyloidogenic.
8
N-terminal
APP enzymolysis pathways
9
Formation of amyloid fibril
Schematic representation of amyloid fibril
David J. Hayne, SinChun Lim and Paul S. Donnelly.Chem .Soc .Rev.2014;
10
3D structure of Aβ42 fibrils
Structural studies using fibrils formed from Aβ 42 peptides have
given insight into the 3D structure of Aβ 42 fibrils .
David J. Hayne, SinChun Lim and Paul S. Donnelly.Chem. Soc. Rev.2014;
11
Presenilin(PS)
Presenilin transmembrane structure diagram
PS-1 PS-2
顾拥军，孙凤艳， J.Life Science,1997;5,9
extracellular
intracellular
HL-VIPS-1:70%~80% of FAD is related to the mutations in PS-1.(age of onset:40~50)PS-2:Some of FAD is related to the mutations in PS-2.(age of onset:50~60)
The exact three-dimensional structure and function of PS remain unkonwn.
12
APOE
ApoE4 in AD Pathogenesis
Yadong Huang ,Lennart Mucke.J.Cell.2012， 1204-1223
The apoE proteolysis hypothesis suggests that, in response to stress or injuries, neuronal apoE expression is triggered to facilitate neuronal repair. However, neuronal apoE undergoes proteolytic cleavage, with apoE4 being more susceptible to the cleavage than apoE3, resulting in the formation of neurotoxic fragments. The apoE4 fragments enter the cytosol and cause mitochondrial impairment and cytoskeletal disruption.
13
Analysis pipeline
The information of AD ralated genes contain: genesymbol 、 geneID 、 ensembl ID proteinID 、 ensembl ID2Chromosomeinfo
map to the chromosome
14
Preliminary data processing
TGM6 、 SNAR-I 、 STK11 、 CLMN 、 UTS2D 、 PGAM5P1 、 ITGA1 、 OSTNIL1-RAP 、 LEMD2 、 VSNL1 、 Sec11C 、 PPP1R3B 、 SLC28A1 、 MPP7 、 CAMK4 、 CACNA1G 、
ARHGAP20 、 RELN 、 PCDH11X 、 LIPC 、 RP11-341A22.2 、 PRRC2C 、 PPP1R37 、 RFC3 、 HRK 、 MS4A4A 、 MS4A4E 、 TREM 、 BIN1 、 SAP30L 、 PVRL2 、 EDIL3 、 MEGF10 、
CD2AP 、 CDON 、 FAM113B 、 ARID1B 、 ELMO1 、 VLDLR 、 MMP12 、 ANKRD55 、 ANO4 、 GAB2 、 ITGA6 、 FMN2 、 ZNF592 、 APOE 、 BCHE 、 ZNF224 、 MSRA 、 CRADD 、 ST18 、 GEMC1 、 SLC9A9 、 AFF1 、 BCAS3 、 DISC1 、 PIK3R1 、 NKAIN2 、 CCDC50 、 ALPK3 、 DCHS2 、 FLJ45256 、 AC079250.1 、 FLJ33630 、 STK24 、 PAX2 、 CCDC134 、
STK32B 、 RP11-572M11.4 、 KCNV2 、 HECW1 、 VAT1L 、 TOMM40 、 RP11-291J9.2 、 SP6 、 MRPL10 、 OSBPL7 、 GPC6 、 ADAMTS9 、 EPHA1 、 CSMD1 、 TREM2 、 POLN 、
SLC4A8 、 ATXN7L1 、 SORL1 、 MIR1275 、 MIR1275 、 PPAPDC1A 、 GABRG3 、 PICALM 、CLU 、 APOC1 、 PDE7B 、 NUAK1 、 PARVB 、 SASH1 、 ZNF320 、 RIMBP2 、 EFNA5 、
MAN2A1 、 DMXL1 、 MOBP 、 FRMD4A 、 LOC390956 、 LOC390958 、 MYO16 、 MTHFD1L 、 DIP2C 、 NCS1 、 CYCS 、 LIMS2 、 CNTNAP2 、 AC015804.1 、 LOC100129500 、 C12orf75 、 CR1 、 FLJ37543 、 GRIN3B 、 BZW2 、 TSPAN13 、 TSPAN13 、 EFR3A 、 RP11-
242G20.2 、 TTLL7 、 MLN 、 NCR2 、 MS4A6A 、 LUZP2 、 CUGBP2 、 HMHA1 、 PCNX 、 SPON1 、 RRAS2 、 CEACAM16 、 CTNNA2 、 AC110611.1 、 NFIB 、 PLEKHG1 、 EXOC4 、
RNFT2 、 SLC4A1AP 、 BCL3 、 AC008541.1 、 MS4A 、 MMP3 、 AP003097.1 、 PSMA1 、 SLC2A9 、 CD33 、 GLIS3 、 EPC2
The AD related genes (GWASstudies)
www.genome.gov/GWAStudies
Number:153
15
Gene frequency statistics
Frequency in GWASstudies Genes
20 APOE
13 TOMM40
7 BIN1
6 PVRL2
4 PICALM 、 CLU 、 APOC1
3 CR1
2 SLC2A9 、 CD33 、 GLIS3 、 EPC2
1 POLN 、 MS4A 、 PAX2 、 TREM2
、 MLN…(140)
APOE 、 TOMM40 、 APOC1: Genes locate on the chromosome 19.TREM2: Some other studies have found that the mutation of TREM2 could increase the risk of AD.
16
1. Chromosome 19 has 14 AD ralated genes.
Gene location on chromosome
APOE
2. Chromosome 6 , 5 and 11 also have 13,10,9 AD related genes respectively.
So if there are genes like APOE locate on them?
3. Chromosome 21 has no AD related genes on it ,but APP is on it. And Why?
17
Three FDA approved agents for Imaging of Aβ Plaques
18
(1)
Amyvid(Diaryl alkene analogs)
Company : Eli Lilly Year : 2012.10
(2)
Vizaml(Planar heteroaromatic analogs)
Company:General Electric Company Year:2013.10
(3)
Company:Pfizer
Year:2014.3
Florbetaben(Diaryl alkene analogs)
They are just the agents to detect and specific binding to Aβ ,not the drugs to treat or alleviate AD symptoms.
The information of the 3 agents
N. S. Mason, C. A. Mathis and W. E. Klunk, J. LabelledCompd. Radiopharm., 2013, 56, 89.
19
PET(Positron emission tomography,正电子发射计算机断层扫描 ) is a non-invasive molecular imaging technique that relies on the detection of radioactivity emitted from a positron-emitting isotope that is incorporated into a molecular tracer or imaging agent. The emitted positron annihilates releasing two gamma photons travelling in opposite directions. Detection of the emitted photons allows the generation of an image with a spatial resolution of 3–5 mm with high sensitivity.
PET
http://en.wikipedia.org/wiki/Positron_emission_tomography
20
Axial slices of Vizaml scans are shown for 2 representative subjects, cognitively normal control with low tracer
retention (top) and AD patient with high tracer retention in cortex relative to cerebellum, reflecting widespread fibrillar
amyloid (bottom).
Landau SM,Breault C,Joshi AD,Pontecorvi M,Mathis CA,Jagust WJ,Mintun MA,J Nucl Med,2013;54:70-7.
The image of PET
21
Summary
The full details of the role Aβ plaques, APOE, PS-1, and PS-2 play in congnitive impair in Alzheimer’s Disease remain a mystery.
The development of these agents for imaging of Aβ plaques might provide the means for early non-invasive detection of Aβ plaques in AD and pre-AD subjects.
AD ralated genes are abundant at chromosome 19. Maybe there are genes like APOE locate on chromosome 6,5 and 11.
22
Acknowledge
Prof. WuProf. YeXudong ZouYang Wang……
