Neurotoxicity of human serum amyloid P component
Lead Research Organisation:
University College London
Department Name: Neuroscience Physiology and Pharmacology
Abstract
Alzheimer's disease (AD) affects about 500,000 individuals in the UK and is a major medical, social and economic burden, currently costing more than £17 billion per year. Increasing age is the strongest risk factor for typical AD and case numbers are estimated to rise by about 40% and about 150%, respectively, over the next 15 and 45 years; there may be 40 million cases worldwide by 2050. The UK Coalition Government has stated that "there is therefore a pressing need to prioritise dementia research". Existing drugs provide short term symptomatic benefit but none affect the inexorable progression of AD. Treatment which slowed progress would reduce the suffering of patients and carers and eliminate many cases as ageing individuals died from other causes before being crippled by dementia. The economic impact of such disease modifying treatment would be enormous.
The brain in AD contains an abnormally increased amount of a normal blood protein called serum amyloid P component (SAP). The cerebrospinal fluid bathing the brain contains SAP at only about one thousandth of the level in the blood. However in AD patients the brain always contains abnormal, solid protein fibres to which SAP binds. SAP thus accumulates in the brain and is at an abnormally high concentration around these fibres. The brain cells, called neurones, close to the SAP coated fibres are damaged and die, and the loss of their functions causes dementia. The reasons why these neurones die are poorly understood and, despite billions of pounds spent on their development, drugs which aim to prevent formation of the fibres themselves or to remove them, have not, as yet, been effective.
In a striking new finding, we have lately demonstrated convincingly that highly purified SAP isolated from human blood is directly damaging to brain cells. Exposure to human SAP produces abnormalities in the communications between neurones which closely resemble the defects typical of AD. Exposure to even modest SAP concentrations, less than those in the blood, eventually kills neurones. There is thus a very strong possibility that SAP may contribute significantly to the damage to the brain which is responsible for dementia in AD and possibly also other conditions.
We have developed a new medicine which, when it is given to patients, rapidly removes almost all the SAP from the blood. SAP is not produced in the brain and only comes from the blood. If there is no SAP in the blood there can be no SAP in the brain. Indeed, in a preliminary clinical study published in 2009, we gave the new drug, known as CPHPC, to 5 patients with AD and showed that all SAP completely disappeared from their cerebrospinal fluid. The trial was only for 3 months and thus much too short to show whether removal of SAP was beneficial to the patients. However, importantly, both administration of the drug and the depletion of SAP which it produces have been completely safe, even when continued for many years in patients with another disease, known as amyloidosis, in which SAP is involved.
The purpose of the present research is to understand as completely as possible the way in which SAP damages the brain so that we can design clinical studies of CPHPC and removal of SAP with the best chance of showing convincingly that they protect or even improve brain functions. We will therefore thoroughly investigate the effects of SAP on brain cells and their functions. We will examine the amount of SAP required to cause damage and the length of time it takes, looking at both the function of brain cells and the structure of the brain. We will also investigate whether the drug, CPHPC, can protect neurones from damage by SAP in our experimental systems. If this is achieved it will provide irresistible support for funding of appropriate clinical studies in patients with AD and possibly also other forms of dementia in which SAP could be involved.
The brain in AD contains an abnormally increased amount of a normal blood protein called serum amyloid P component (SAP). The cerebrospinal fluid bathing the brain contains SAP at only about one thousandth of the level in the blood. However in AD patients the brain always contains abnormal, solid protein fibres to which SAP binds. SAP thus accumulates in the brain and is at an abnormally high concentration around these fibres. The brain cells, called neurones, close to the SAP coated fibres are damaged and die, and the loss of their functions causes dementia. The reasons why these neurones die are poorly understood and, despite billions of pounds spent on their development, drugs which aim to prevent formation of the fibres themselves or to remove them, have not, as yet, been effective.
In a striking new finding, we have lately demonstrated convincingly that highly purified SAP isolated from human blood is directly damaging to brain cells. Exposure to human SAP produces abnormalities in the communications between neurones which closely resemble the defects typical of AD. Exposure to even modest SAP concentrations, less than those in the blood, eventually kills neurones. There is thus a very strong possibility that SAP may contribute significantly to the damage to the brain which is responsible for dementia in AD and possibly also other conditions.
We have developed a new medicine which, when it is given to patients, rapidly removes almost all the SAP from the blood. SAP is not produced in the brain and only comes from the blood. If there is no SAP in the blood there can be no SAP in the brain. Indeed, in a preliminary clinical study published in 2009, we gave the new drug, known as CPHPC, to 5 patients with AD and showed that all SAP completely disappeared from their cerebrospinal fluid. The trial was only for 3 months and thus much too short to show whether removal of SAP was beneficial to the patients. However, importantly, both administration of the drug and the depletion of SAP which it produces have been completely safe, even when continued for many years in patients with another disease, known as amyloidosis, in which SAP is involved.
The purpose of the present research is to understand as completely as possible the way in which SAP damages the brain so that we can design clinical studies of CPHPC and removal of SAP with the best chance of showing convincingly that they protect or even improve brain functions. We will therefore thoroughly investigate the effects of SAP on brain cells and their functions. We will examine the amount of SAP required to cause damage and the length of time it takes, looking at both the function of brain cells and the structure of the brain. We will also investigate whether the drug, CPHPC, can protect neurones from damage by SAP in our experimental systems. If this is achieved it will provide irresistible support for funding of appropriate clinical studies in patients with AD and possibly also other forms of dementia in which SAP could be involved.
Technical Summary
We have lately demonstrated that exposure to the normal human plasma protein, serum amyloid P component (SAP), in vitro or in vivo, damages cerebral neurones causing major abnormalities of synaptic transmission. The cerebrospinal fluid (CSF) concentration of SAP is about 1/1000 of the plasma value but the SAP content of the brain is always abnormally increased in Alzheimer's disease (AD) by the avid but reversible binding of SAP to amyloid fibrils and neurofibrillary tangles. The local SAP concentration around these focal lesions must be greater than normal. We propose that long term exposure to even modestly increased levels of human SAP, and/or transient or intermittent exposure to higher levels, may contribute to neuronal damage responsible for cognitive loss. We have reported that our novel bis(D-proline) drug, CPHPC, which depletes circulating SAP, also removes all SAP from the CSF in patients with AD. We will now fully characterise the time and dose dependence, and the specificity, of the effects of our unique, GMP grade, 100% pure human SAP on paired pulse ratio, long term potentiation and neuronal viability in organotypic hippocampal slices, and study cellular binding and entry of SAP and its nuclear localisation. We will investigate the time and SAP dose dependence of abnormalities of cerebral synaptic transmission and cognitive function in two different lines of human SAP transgenic mice expressing, respectively, normal human range and five fold higher human SAP concentrations, and will characterise associated neuropathology compared to wild type littermates. Modulation by transgenic human SAP of abnormalities of synaptic transmission, cognition and neuropathology in the TASTPM mouse model of AD will also be studied. Finally we will assess the capacity of depletion of human SAP, produced by treatment with CPHPC, to abrogate any or all of the neurological abnormalities observed in human SAP transgenic mice.
Planned Impact
Alzheimer's disease (AD) is the fourth most common cause of death in the developed world but with a vastly disproportionate social and economic cost. Its pathogenesis, including the mechanism responsible for the neurodegeneration which causes cognitive loss, is poorly understood and there are no disease modifying treatments. None of the therapeutic approaches currently in publicly disclosed development are showing promise due to lack of efficacy and/or unacceptable toxicity in clinical trials to date.
Based on its role in the formation and persistence of the neuropathological hallmarks of AD, the amyloid plaques and neurofibrillary tangles, Pepys previously identified and validated human serum amyloid P component (SAP), a normal universally present plasma protein, as a therapeutic target. He therefore developed a novel, safe and potent drug, CPHPC, which completely depletes human SAP from the blood and the brain in patients with AD. In new experiments we have now demonstrated rigorously for the first time that human SAP is potently neurotoxic in vitro and in vivo. The present project, which will confirm and extend these observations and elucidate their mechanism, will compellingly support therapeutic targeting of SAP in AD.
Our findings will have an immediate and powerful impact on the pharmaceutical industry. The IP covering SAP as a therapeutic target in AD, CPHPC itself and related molecules, and the pharmacological mechanism by which CPHPC depletes SAP are all owned by a UCL spin out company, Pentraxin Therapeutics Ltd, which was created for this purpose. The experimental results we will generate will, we hope, compellingly encourage academic and/or commercial funding of clinical studies of CPHPC in AD and possibly other neurodegenerative causes of cognitive loss. Our findings will also arouse intense interest in the pharmaceutical industry generally, unrelated to our existing compounds, expertise and IP.
Disease modifying treatments for AD are urgently required and this has been identified by the UK government as its highest biomedical research priority. If our work leads to such new treatment, its impact on this massive unmet medical need will be enormous. The contribution to human health is obvious. The associated benefits to patients, carers and society will enable huge savings on care costs coupled with national wealth benefits through pharmaceutical industry provision of effective drugs world wide.
Based on its role in the formation and persistence of the neuropathological hallmarks of AD, the amyloid plaques and neurofibrillary tangles, Pepys previously identified and validated human serum amyloid P component (SAP), a normal universally present plasma protein, as a therapeutic target. He therefore developed a novel, safe and potent drug, CPHPC, which completely depletes human SAP from the blood and the brain in patients with AD. In new experiments we have now demonstrated rigorously for the first time that human SAP is potently neurotoxic in vitro and in vivo. The present project, which will confirm and extend these observations and elucidate their mechanism, will compellingly support therapeutic targeting of SAP in AD.
Our findings will have an immediate and powerful impact on the pharmaceutical industry. The IP covering SAP as a therapeutic target in AD, CPHPC itself and related molecules, and the pharmacological mechanism by which CPHPC depletes SAP are all owned by a UCL spin out company, Pentraxin Therapeutics Ltd, which was created for this purpose. The experimental results we will generate will, we hope, compellingly encourage academic and/or commercial funding of clinical studies of CPHPC in AD and possibly other neurodegenerative causes of cognitive loss. Our findings will also arouse intense interest in the pharmaceutical industry generally, unrelated to our existing compounds, expertise and IP.
Disease modifying treatments for AD are urgently required and this has been identified by the UK government as its highest biomedical research priority. If our work leads to such new treatment, its impact on this massive unmet medical need will be enormous. The contribution to human health is obvious. The associated benefits to patients, carers and society will enable huge savings on care costs coupled with national wealth benefits through pharmaceutical industry provision of effective drugs world wide.
Publications
Cummings DM
(2017)
Neuronal and Peripheral Pentraxins Modify Glutamate Release and may Interact in Blood-Brain Barrier Failure.
in Cerebral cortex (New York, N.Y. : 1991)
Cummings DM
(2015)
First effects of rising amyloid-ß in transgenic mouse brain: synaptic transmission and gene expression.
in Brain : a journal of neurology
Edwards A
(2021)
Additive manufacturing of multielectrode arrays for biotechnological applications
in Materials Advances
Hardy JG
(2015)
Multiphoton microfabrication of conducting polymer-based biomaterials.
in Journal of materials chemistry. B
Matarin M
(2015)
A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology.
in Cell reports
Paulin JJ
(2016)
Large and Small Dendritic Spines Serve Different Interacting Functions in Hippocampal Synaptic Plasticity and Homeostasis.
in Neural plasticity
Witton J
(2015)
Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.
in Nature neuroscience
Description | ARUK Senior Fellowship (Dervis Salih in Edwards lab) |
Amount | £330,000 (GBP) |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2013 |
End | 09/2016 |
Description | Dana Foundation, New York, Dementia Research Grant |
Amount | $250,000 (USD) |
Organisation | Dana Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start |
Description | MRC research grant |
Amount | £975,488 (GBP) |
Funding ID | MR/J011851/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 01/2012 |
End | 12/2014 |
Description | Modelling Alzheimer's disease pathology in 3D neuronal cultures and organotypic slices and the role of microglia |
Amount | £211,116 (GBP) |
Funding ID | ARUK-PG2017B-17 |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2017 |
End | 07/2019 |
Description | Multiple methods for modelling Alzheimer's disease |
Amount | £30,000 (GBP) |
Funding ID | ARUK-NSG2016-4 |
Organisation | Alzheimer's Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2016 |
End | 09/2016 |
Description | NIHR Strategic Award via UCLH/UCL BRC |
Amount | £2,750,798 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | |
End | 11/2021 |
Description | NIHR UCLH/UCL BRC Core Support for Wolfson Drug Discovery Unit |
Amount | £1,000,000 (GBP) |
Organisation | National Institute for Health Research |
Department | UCLH/UCL Biomedical Research Centre |
Sector | Academic/University |
Country | United Kingdom |
Start | 03/2017 |
End | 03/2022 |
Description | NIHR UCLH/UCL BRC Core Support for Wolfson Drug Discovery Unit (Supplement) |
Amount | £150,000 (GBP) |
Organisation | National Institute for Health Research |
Department | UCLH/UCL Biomedical Research Centre |
Sector | Academic/University |
Country | United Kingdom |
Start | 11/2018 |
End | 03/2022 |
Title | Mouseac |
Description | Genome-wide gene expression of 5 mouse models of Alzheimer's disease over the life of mice with either amyloid or Tau pathology and comparison to wild-type mice |
Type Of Material | Database/Collection of data |
Year Produced | 2014 |
Provided To Others? | Yes |
Impact | This database has been enthusiastically received by colleagues and is informing our research on Pentraxins and other areas. The initial analysis of the database is the subject of a 'Resource' being reconsidered by Neuron for publication The data base is now being updated with APP knockin data and Jonathan Brenton is very involved in this |
URL | http://www.mouseac.org |
Description | Gene expression in mouse models of Alzheimer's disease |
Organisation | GlaxoSmithKline (GSK) |
Country | Global |
Sector | Private |
PI Contribution | The upkeep of the various mouse models Preparation of RNA and protein for analysis Background expertise on the mouse models Histology |
Collaborator Contribution | Genetics expertise Organisation and funding of initial gene expression analysis Supply of Microarrays Salary support This partnership has arisen partly out of contact through ARUK network |
Impact | 2 publications out plus one in press - see publications list |
Start Year | 2013 |
Description | Gene expression in mouse models of Alzheimer's disease |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | The upkeep of the various mouse models Preparation of RNA and protein for analysis Background expertise on the mouse models Histology |
Collaborator Contribution | Genetics expertise Organisation and funding of initial gene expression analysis Supply of Microarrays Salary support This partnership has arisen partly out of contact through ARUK network |
Impact | 2 publications out plus one in press - see publications list |
Start Year | 2013 |
Description | The role of Serum Amyloid P component in the CNS |
Organisation | Royal Free Hospital |
Country | United Kingdom |
Sector | Hospitals |
PI Contribution | As experts in synaptic transmission and plasticity we use a range of electrophysiological and imaging techniques to study the effects of Serum Amyloid P component (SAP) in the hippocampus. I am also supervising the testing of cognitive behaviours in mice expressing human SAP and also the effect of the drug CPHPC which binds to SAP resulting in its clearance from plasma. We are finding some very interesting and potentially important effects suggesting that SAP has direct effects on neurones even in the absence of plaques. |
Collaborator Contribution | Sir Mark Pepys is the world expert on Serum Amyloid P component (SAP). SAP has previously largely been studied in the periphery in relation to amyloidosis however due to its presence on amyloid plaques in Alzheimer's disease Mark Pepys became interested in understanding its role in the brain and the possibility that its removal may be a potential treatment for Alzheimer's disease. Mark Pepys supplies the various mice used in the project, the compounds (purified human SAP and CPHPC) and also his vast expertise in the chemistry of these molecules and the previous history of research into their functions. Other collaborators include Professor Sebastian Brandner, immunohistochemistry; Professor Francesca Cordeiro, retinal detection of neurodegeneration and Paul Simons andd Raya Al-Shawi experts in all aspects of the mouse breeding and work in Professor Pepys lab on this project. |
Impact | MRC grant January 2012-2013 ~£1.2 million specifically funds this collaboration Cummings et al., Neuronal and Peripheral Pentraxins Modify Glutamate Release and may Interact in Blood-Brain Barrier Failure Cerebral Cortex, June 2017;27: 3437-3448 |
Start Year | 2011 |
Description | The role of Serum Amyloid P component in the CNS |
Organisation | University College London |
Department | Institute of Neurology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | As experts in synaptic transmission and plasticity we use a range of electrophysiological and imaging techniques to study the effects of Serum Amyloid P component (SAP) in the hippocampus. I am also supervising the testing of cognitive behaviours in mice expressing human SAP and also the effect of the drug CPHPC which binds to SAP resulting in its clearance from plasma. We are finding some very interesting and potentially important effects suggesting that SAP has direct effects on neurones even in the absence of plaques. |
Collaborator Contribution | Sir Mark Pepys is the world expert on Serum Amyloid P component (SAP). SAP has previously largely been studied in the periphery in relation to amyloidosis however due to its presence on amyloid plaques in Alzheimer's disease Mark Pepys became interested in understanding its role in the brain and the possibility that its removal may be a potential treatment for Alzheimer's disease. Mark Pepys supplies the various mice used in the project, the compounds (purified human SAP and CPHPC) and also his vast expertise in the chemistry of these molecules and the previous history of research into their functions. Other collaborators include Professor Sebastian Brandner, immunohistochemistry; Professor Francesca Cordeiro, retinal detection of neurodegeneration and Paul Simons andd Raya Al-Shawi experts in all aspects of the mouse breeding and work in Professor Pepys lab on this project. |
Impact | MRC grant January 2012-2013 ~£1.2 million specifically funds this collaboration Cummings et al., Neuronal and Peripheral Pentraxins Modify Glutamate Release and may Interact in Blood-Brain Barrier Failure Cerebral Cortex, June 2017;27: 3437-3448 |
Start Year | 2011 |
Description | UCL DemNet (Dementia Network) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | I set up a Dementia Network across UCL which is run from my lab. Annual one day symposium, largely internal to UCL 130-160 participants each year for 4 years Approximately 6 journal clubs or other across UCL discussion meetings Mailing list informing members of seminars, events, funding opportunities and generally enhancing communication flow Website still needs to be set up but it is a very active group including researchers across all UCL Institutes. Extremely active interactions; increased collaborations between groups |
Year(s) Of Engagement Activity | 2011,2012,2013,2014 |
Description | Visiting students |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | Yes |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Most of the students have gone on to do Biomedical Sciences or Medicine and generally they keep in touch for sometime during their degrees. They of course also discuss research with their parents and families and often the parents come and visit the lab also. as above |
Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014 |
URL | http://in2scienceuk.org |