WO2006003414A2 - Biomarkers of alzheimer's disease - Google Patents
Biomarkers of alzheimer's disease Download PDFInfo
- Publication number
- WO2006003414A2 WO2006003414A2 PCT/GB2005/002592 GB2005002592W WO2006003414A2 WO 2006003414 A2 WO2006003414 A2 WO 2006003414A2 GB 2005002592 W GB2005002592 W GB 2005002592W WO 2006003414 A2 WO2006003414 A2 WO 2006003414A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- gsk
- antibody
- disease
- alzheimer
- diagnosis
- Prior art date
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2814—Dementia; Cognitive disorders
- G01N2800/2821—Alzheimer
Definitions
- This invention relates to the diagnosis of Alzheimer's disease and more particularly to reliable diagnosis at early stages of this disease.
- AD Alzheimer's disease
- the progress being made in the understanding of AD and related disorders at a molecular level is not being matched by progress in clinical assessment. Diagnosis is performed by clinical interview with supplementary investigations to exclude rare treatable causes of confusion. As specific treatments are generated for prevention or modification of AD, the limitations in diagnosing the disease will become more clinically relevant and might substantially delay effective assessment and utilisation of treatments.
- AD and fronto-temporal dementia are part of the group of disorders known as the tauopathies characterised by aggregates of highly phosphorylated tau protein.
- GSK-3 glycogen synthase kinase-3
- CDK5 glycogen synthase kinase-5
- GSK-3 has been shown to co-localise with neurofibrillary tangles
- p25 the precursor of CDK5
- CDK5 has been shown to be present to excess in post mortem AD brain.
- post-mortem studies pose the question as to whether these observations are a cause or an effect of neurodegeneration; an important issue carrying direct therapeutic implications.
- GSK-3 as a drug target for therapies of diseases of the central nervous system. They suggest that the active form of GSK-3 ⁇ is increased in AD brain, although they state that increased levels of total GSK-3 have not been consistently observed in AD brain. Nevertheless, they go on to suggest that GSK-3 inhibition could be of therapeutic benefit in AD.
- GSK-3 inhibitors in therapy of various diseases, including AD, is also discussed by Eldar-Finkelman (2002; Trends in Molecular Medicine 8, 126-132).
- GSK-3 has never been suggested as a suitable prognostic or diagnostic marker for AD.
- AD Alzheimer's disease
- WO 2004/027429 discloses a method and diagnostic kit for diagnosing AD, among patients with MCI, by testing for the enzyme glutamine synthetase in blood. Since glutamine synthetase is astrocyte-specific, it could simply be an indicator of neuronal damage.
- a method for the prognosis or diagnosis of AD comprising measuring levels of GSK-3 in cells or body fluid in a sample taken from a human subject.
- the total amount of GSK-3 isotypes may be measured and compared with controls. This can provide an indication of whether a subject has or is likely to develop AD.
- the levels of both active and inactive GSK-3 are measured.
- An increase in active GSK-3 indicates a likelihood of AD, whereas levels of inactive GSK-3 remain unaltered.
- a positive indication of AD is determined by detecting a 20% increase in GSK-3 protein or activity. This can indicate the presence or the likelihood of future development of AD.
- MCI mild cognitive impairment
- sample tested is serum or plasma. This allows a particularly simple method of testing for the presence of GSK-3, without the need for an invasive procedure.
- kits for use in a test for the prognosis or diagnosis of Alzheimer's disease comprising at least one of the following antibodies: antibody to GSK-3 and antibody to active GSK-3.
- the antibody to GSK-3 is anti-GSK-3 ⁇ / ⁇ and the antibody to active GSK-3 is anti-GSK-3 ⁇ / ⁇ Tyr 216/219.
- the kit may further comprise antibody to inactive GSK-3, which is preferably anti-GSK-3 ⁇ / ⁇ Ser 21/9.
- anti-GSK-3 antibody or anti-inactive GSK-3 antibody for use in a test for the diagnosis or prognosis of Alzheimer's disease.
- anti-GSK-3 antibody anti-inactive GSK-3 antibody in the manufacture of a kit for use in a test for the diagnosis or prognosis of Alzheimer's disease.
- GSK-3 protein both the alpha and beta isoforms of the enzyme
- active phosphorylated at Tyr216/219
- inactive enzyme phosphorylated at Ser9/21
- Fresh venous blood is collected in a BD vacutainer K3E 15% tubes.
- the blood is spun at 3000rpm for 8min and the plasma is aliquoted and stored at -7O 0 C.
- the remaining buffy coat is carefully collected using a P200 pipette (some red blood cells collected is acceptable).
- the buffy coat is transferred to a clean micro tube and stored at -2O 0 C until use.
- the buffy coat sample is defrosted and added to 10ml red cell lysis buffer (lOmMTris, 5mMMgCl 2 and 1OmMNaCl pH 7.6) in a 15ml Falcon tube and left on ice for 30min. The lysed samples are then spun at 2800rpm for lOmin and the supernatant discarded. A further 10ml of lysis buffer is added, the tubes vortexed and then left on ice for a further 20min.
- 10mMTris 5mMMgCl 2 and 1OmMNaCl pH 7.6
- the samples are once more spun at 2800rpm for lOmin and the supernatant is discarded.
- 300 ⁇ l of 2x sample buffer is added and transferred from the Falcon tube to a micro tube and heated at 100 0 C for lOmin.
- lO ⁇ l of the lysed sample is loaded onto a 10% SDS-PAGE gel and separated at 150V for 60min.
- the proteins are transferred to a substrate, which is subsequently blotted and probed overnight at 4°C with ⁇ -actin AC-15 antibody for normalisation to total protein (Sigma), GSK-3 ⁇ / ⁇ antibody for total GSK-3 protein (Bioquote), GSK-3 ⁇ / ⁇ Ser 21/9 antibody for inactive GSK-3 and GSK-3 ⁇ / ⁇ Tyr 216/219 antibody for active GSK-3 (Signal Transduction). Bands were detected with a chemiluminescence Western detection kit (Amersham). The blots are then scanned using a Bio-Rad GS710 scanner, and the optical density of immunoreactive bands was quantified using the Bio-Rad Quantity One image analysis system.
- GSK-3 protein both alpha and beta isoforms
- activity as represented by the Tyr 216/219 phospho-specific antibody
- levels of inactive GSK-3 as represented by the Ser 21/9 antibody
- a measure of about 20% or more of GSK-3 protein or activity is an indication of the presence or likelihood of future development of AD.
- GSK-3 protein and activity in peripheral samples such as white cells or lymphocytes therefore provides effective diagnosis, early detection and staging of Alzheimer's disease and related dementias.
- the assessment of GSK-3 protein and activity can be used as an early diagnostic marker test to distinguish people with AD from other conditions that can be confused with it (e.g. other conditions that may involve memory loss such as depression or anxiety or other disorders causing dementia, such as vascular dementia or dementia with Lewy bodies). It may also assist in determining whether a person with MCI is likely to progress to dementia, or to monitor the progression of disease in response to treatments (currently only symptomatic markers are available). This marker will therefore help in the monitoring of the effects of therapies designed for disease modification and can be used as a surrogate marker for disease modification in clinical trials. It may also help in predicting which patents with AD are most likely to respond to therapies.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP05756942A EP1763674A2 (en) | 2004-07-02 | 2005-07-01 | Biomarkers of alzheimer's disease |
AU2005258926A AU2005258926A1 (en) | 2004-07-02 | 2005-07-01 | Biomarkers of Alzheimer's disease |
CA002571692A CA2571692A1 (en) | 2004-07-02 | 2005-07-01 | Biomarkers of alzheimer's disease |
US11/630,769 US20080076140A1 (en) | 2004-07-02 | 2005-07-01 | Biomarkers of Alzheimer's Disease |
JP2007518700A JP2008504551A (en) | 2004-07-02 | 2005-07-01 | Biomarkers for Alzheimer's disease |
BRPI0512948-6A BRPI0512948A (en) | 2004-07-02 | 2005-07-01 | biomarkers of alzheimer's disease |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0414894.6 | 2004-07-02 | ||
GBGB0414894.6A GB0414894D0 (en) | 2004-07-02 | 2004-07-02 | Biomarkers of alzheimer's disease |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2006003414A2 true WO2006003414A2 (en) | 2006-01-12 |
WO2006003414A3 WO2006003414A3 (en) | 2006-03-16 |
Family
ID=32843494
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2005/002592 WO2006003414A2 (en) | 2004-07-02 | 2005-07-01 | Biomarkers of alzheimer's disease |
Country Status (9)
Country | Link |
---|---|
US (1) | US20080076140A1 (en) |
EP (1) | EP1763674A2 (en) |
JP (1) | JP2008504551A (en) |
CN (1) | CN101010589A (en) |
AU (1) | AU2005258926A1 (en) |
BR (1) | BRPI0512948A (en) |
CA (1) | CA2571692A1 (en) |
GB (1) | GB0414894D0 (en) |
WO (1) | WO2006003414A2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007138408A1 (en) | 2006-05-25 | 2007-12-06 | Ge Healthcare Limited | 11c/18 f-labeled inhibitors of glycogen synthase kinase-3 |
WO2009074331A2 (en) * | 2007-12-11 | 2009-06-18 | Julius-Maximilians-Universität Würzburg | Early and differential diagnosis test for alzheimer's disease |
EP2270201A1 (en) * | 2009-07-01 | 2011-01-05 | National Tsing Hua University | Detection of unhealthy cell and uses thereof |
US8753607B2 (en) | 2008-03-21 | 2014-06-17 | Manuela G. Neuman | Methods and kits for the differential diagnosis of Alzheimer's disease versus frontotemporal dementia and for the diagnosis of frontotemporal dementia, comprising FAS-L and CK 18 as biomarkers |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120040361A1 (en) * | 2010-07-22 | 2012-02-16 | National Tsing Hua University | Methods and compositions for detection of lethal system and uses thereof |
CN104237526B (en) * | 2013-06-18 | 2016-08-17 | 磁量生技股份有限公司 | A kind of system detecting Alzheimer disease risk |
US20170102398A1 (en) * | 2014-03-05 | 2017-04-13 | Humanetics Corporation | Predicting and reducing cognitive decline based on gsk-3 levels |
CN104698188A (en) * | 2015-03-04 | 2015-06-10 | 华中科技大学 | Dot blotting method for detecting activity of GSK-3beta proteins of human blood platelets |
CN111323597A (en) * | 2018-12-14 | 2020-06-23 | 陈志成 | Methods, kits and methods of screening compounds for detecting MCI and/or AD in a subject |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005108582A1 (en) * | 2004-05-07 | 2005-11-17 | Garvan Institute Of Medical Research | DETECTING DISEASE ASSOCIATION WITH ABERRANT GLYCOGEN SYNTHASE KINASE 3β EXPRESSION |
-
2004
- 2004-07-02 GB GBGB0414894.6A patent/GB0414894D0/en not_active Ceased
-
2005
- 2005-07-01 WO PCT/GB2005/002592 patent/WO2006003414A2/en active Application Filing
- 2005-07-01 EP EP05756942A patent/EP1763674A2/en not_active Withdrawn
- 2005-07-01 JP JP2007518700A patent/JP2008504551A/en not_active Withdrawn
- 2005-07-01 AU AU2005258926A patent/AU2005258926A1/en not_active Abandoned
- 2005-07-01 CN CNA2005800225150A patent/CN101010589A/en active Pending
- 2005-07-01 US US11/630,769 patent/US20080076140A1/en not_active Abandoned
- 2005-07-01 CA CA002571692A patent/CA2571692A1/en not_active Abandoned
- 2005-07-01 BR BRPI0512948-6A patent/BRPI0512948A/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005108582A1 (en) * | 2004-05-07 | 2005-11-17 | Garvan Institute Of Medical Research | DETECTING DISEASE ASSOCIATION WITH ABERRANT GLYCOGEN SYNTHASE KINASE 3β EXPRESSION |
Non-Patent Citations (5)
Title |
---|
BEASLEY CLARE ET AL: "Glycogen synthase kinase-3beta immunoreactivity is reduced in the prefrontal cortex in schizophrenia" NEUROSCIENCE LETTERS, vol. 302, no. 2-3, 20 April 2001 (2001-04-20), pages 117-120, XP002359899 ISSN: 0304-3940 * |
FERRER I ET AL: "Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration." ACTA NEUROPATHOLOGICA, vol. 104, no. 6, December 2002 (2002-12), pages 583-591, XP002359897 ISSN: 0001-6322 * |
HYE A ET AL: "Proteomics in the early diagnosis of Alzheimer's disease." SOCIETY FOR NEUROSCIENCE ABSTRACT VIEWER AND ITINERARY PLANNER, vol. 2003, 2003, pages Abstract No. 202.24 URL-http://sf, XP009056561 & 33RD ANNUAL MEETING OF THE SOCIETY OF NEUROSCIENCE; NEW ORLEANS, LA, USA; NOVEMBER 08-12, 2003 * |
LEROY KARELLE ET AL: "The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease" ACTA NEUROPATHOLOGICA, vol. 103, no. 2, February 2002 (2002-02), pages 91-99, XP002359896 ISSN: 0001-6322 * |
PEI JIN-JING ET AL: "Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes" JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, vol. 58, no. 9, September 1999 (1999-09), pages 1010-1019, XP009059157 ISSN: 0022-3069 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007138408A1 (en) | 2006-05-25 | 2007-12-06 | Ge Healthcare Limited | 11c/18 f-labeled inhibitors of glycogen synthase kinase-3 |
US8226927B2 (en) | 2006-05-25 | 2012-07-24 | Farhad Karimi | 11C/18F-labeled inhibitors of glycogen synthase kinase-3 |
WO2009074331A2 (en) * | 2007-12-11 | 2009-06-18 | Julius-Maximilians-Universität Würzburg | Early and differential diagnosis test for alzheimer's disease |
WO2009074331A3 (en) * | 2007-12-11 | 2009-08-20 | Univ Wuerzburg J Maximilians | Early and differential diagnosis test for alzheimer's disease |
US8753607B2 (en) | 2008-03-21 | 2014-06-17 | Manuela G. Neuman | Methods and kits for the differential diagnosis of Alzheimer's disease versus frontotemporal dementia and for the diagnosis of frontotemporal dementia, comprising FAS-L and CK 18 as biomarkers |
EP2270201A1 (en) * | 2009-07-01 | 2011-01-05 | National Tsing Hua University | Detection of unhealthy cell and uses thereof |
Also Published As
Publication number | Publication date |
---|---|
CN101010589A (en) | 2007-08-01 |
CA2571692A1 (en) | 2006-01-12 |
AU2005258926A1 (en) | 2006-01-12 |
BRPI0512948A (en) | 2008-04-15 |
US20080076140A1 (en) | 2008-03-27 |
JP2008504551A (en) | 2008-02-14 |
GB0414894D0 (en) | 2004-08-04 |
WO2006003414A3 (en) | 2006-03-16 |
EP1763674A2 (en) | 2007-03-21 |
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