Neurotoxicity of human serum amyloid P component

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.

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.

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.