Serum amyloid P component (SAP) in Alzheimer’s

Lay Summary

A potential new target in Alzheimer’s disease may respond to novel experimental treatment

In a small number of patients with mild Alzheimer’s disease, investigators will test the effects on synaptic transmission of an experimental drug that depletes “serum amyloid P component,” a potential new target for treating

Therapeutic approaches to Alzheimer’s disease (AD) have largely focused on the hallmark abnormal protein deposits called “amyloid.” The protein which forms amyloid in the brain in AD is called Aβ and is derived from a normal nerve cell protein but is produced in increased amounts in AD. The Aβ then forms insoluble fibers which are deposited as plaques in spaces between brain cells. Amyloid plaques are thought to damage brain cell function and eventually lead to cell death but, since no existing treatment removes either Aβ itself or Aβ amyloid from the brain, the precise mechanisms of neurodegeneration in AD are not known. Amyloid occurs in combination with another hallmark of AD, an abnormal form of the protein “tau.” This abnormal protein produces fiber tangles within brain cells, many of which die, possibly due to toxicity of the tangles.

Therapies designed to prevent amyloid from accumulating in the brain or to decrease amyloid plaques once formed so far have not been successful in arresting or treating AD. The collaborating investigators are therefore investigating a totally different approach. Their target is “serum amyloid P component” (SAP). Produced exclusively in the liver, SAP is a normal blood protein present in everybody that enters the brain in only tiny amounts. However it is always present in the cerebrospinal fluid, the liquid which bathes and permeates the brain and spinal cord. SAP has the unique property of binding both to amyloid plaques and to tau tangles, stabilizing and protecting them against the body’s normal clearance mechanism for abnormal protein deposits. Furthermore SAP can enter brain cells, where it tracks to the brain cells’ nucleus. SAP is toxic to brain cells, and, by virtue of the binding of SAP to the amyloid deposits and tangles, there is inevitably an increased brain content of SAP in AD patients compared to normal subjects.

Three different strains of “transgenic” mice containing human SAP all develop “synaptic transmission” abnormalities as they age, according to the investigators’ studies. In other words, over time the animals’ brain cells fail to normally transmit electrochemical signals from one to another at the synapse that connects brain two cells.

A SAP-depleting drug called “CPHPC” has been developed by one of the collaborating investigators (Professor Pepys) and this experimental drug holds promise for targeting SAP as an AD treatment. The drug was developed to treat potentially all diseases caused by or associated with amyloid deposition in the tissues. Apart from Aβ in the brain in AD, about 25 other human proteins are known to form amyloid deposits in different conditions. When the amyloid is in tissue outside the brain, in so-called “systemic amyloidosis”, it can affect any part of the body but never the brain itself. Although systemic amyloidosis and AD are completely unrelated clinically, they have in common the universal presence of amyloid deposits, albeit formed by different proteins, and crucially the universal presence of SAP bound to the amyloid fibers. The experimental drug CPHPC was developed to remove this bound SAP from amyloid. Indeed administration of CPHPC rapidly and almost completely depletes SAP that circulates in the bloodstream in both systemic amyloidosis patients and in AD. However, while CPHPC does not remove all bound SAP from the very large amyloid deposits found in systemic amyloidosis, it will almost certainly remove all SAP from the much smaller, microscopic, amyloid deposits and tangles present in the brain in AD. Indeed experiments in human SAP transgenic mouse models of AD have confirmed the complete disappearance of all SAP from brain amyloid after treatment with CPHPC. Furthermore, in a pilot, proof-of-concept study in five AD patients, the investigators have confirmed that, along with the almost complete depletion of circulating SAP, the protein became undetectable in the cerebrospinal fluid. Importantly neither the drug nor SAP depletion has been found to produce any adverse effects in animal models, in systemic amyloidosis or in AD patients.

The investigators hypothesize, therefore, that CPHPC treatment will safely remove all SAP from the brain, depleting it from the cerebrospinal fluid and stripping it from the amyloid plaques and tau tangles. GlaxoSmithKline has licensed the patents for CPHPC for treating systemic amyloidosis and is supporting the required long-term toxicology studies prior to the investigators’ testing of CPHPC in a larger number of AD patients to see whether it has any effect on the disease process. The investigators recently received funding from the British National Institute for Health Research to undertake this Phase II study of CPHPC in 70 AD patients.

While undertaking these studies, the investigators will use Foundation support to explore whether patients with mild AD have synaptic transmission abnormalities that are similar to those seen in the transgenic mice containing human SAP. If so, they will determine whether these abnormalities lessen or disappear in AD patients who receive the experimental CPHPC drug.

They will study synaptic transmission abnormalities 40 patients with mild AD who are participating in the Phase II study of CPHPC. They will measure patients’ motor cortex excitability, which is a reflection of synaptic transmission functioning. Although motor problems are not a prominent feature of AD, the characteristic amyloid plaques and tangles —and therefore increased SAP amounts—are found in the motor cortex as well as in the cerebral cortex and hippocampus in AD patients. As such, assessing synaptic transmission in the motor cortex is a proxy for assessing this function in the cognitive brain areas that are affected in AD.

The non-invasive technique they will use to assess synaptic transmission is called repetitive transcranial magnetic stimulation (rTMS). Repetitive pulses of an MRI-strength magnetic field are delivered to the motor cortex through a coil placed over the scalp. In AD patients, rTMS of the motor cortex fails to evoke the normal changes in electrical responses. Now the investigators will see whether administration of the SAP-decreasing drug CPHP will reverse that outcome, and evoke more normal motor responses in patients receiving the drug compared to those receiving a placebo.

Investigators will undertake the study of synaptic transmission in 40 patients with mild AD who are participating in the Phase II study of the experimental drug CPHPC funded by the National Institute for Health Research. The participants will include patients who will be receiving CPHPC to reduce SAP levels and an equal number who will be receiving a placebo. The investigators will perform rTMS to assess and compare synaptic plasticity abnormalities in the patients’ motor cortex in those receiving placebo and those receiving CPHPC. They also will determine whether the SAP concentrations in the blood and cerebrospinal fluid correlate with motor cortex activity and therefore synaptic activity. To assess this relationship, patients will undergo “resting state” fMRI (where patients do not perform any tasks while being imaged) to measure motor cortex activity and compare results to SAP values in the blood and the cerebrospinal fluid in both groups of patients.

The investigators anticipate that patients receiving CPHPC, compared to those receiving placebo, will show more normal motor cortex responses to rTMS suggesting improved synaptic transmission; and, that more normal responses are associated with reduced exposure of the brain to SAP.

Potential challenges in this study are minimal. The techniques being used, rTMS and rsfMRI are used regularly in patients. The CPHPC drug is experimental—it has not yet received market approval by the EMA (European Medicines Agency, the counterpart to this country’s federal Food and Drug Administration) but is approved for experimental studies in patients with systemic amyloidosis and has been used safely in such individuals for the past 15 years. To date, the drug has shown no adverse effects in animal model or human studies. Nonetheless, experimental therapies can pose risks, and to date the drug has been only been used in a small number of AD patients. However existing one month regulatory toxicology is sufficient for the present synaptic transmission study. The one-year clinical study will only commence when approval is granted by the MHRA, the UK regulatory equivalent of the FDA, and this awaits completion of legally mandatory 6-month rat toxicology which is currently in progress. During the trial, the investigators will monitor the patients rigorously and continually for any adverse effects.

Significance: If the findings provide initial evidence that CPHPC, by reducing SAP levels, has a positive effect on synaptic transmission in patients with mild AD, the study ultimately could reveal a fundamentally new target and treatment for AD.

Abstract

Serum amyloid P component (SAP) in Alzheimer's

Alzheimer’s disease is one of the major global health challenges and there is no disease modifying therapy for it. Therapeutic approaches to Alzheimer’s disease have focussed on the amyloid cascade but have not been successful. We propose a new target, serum amyloid P component (SAP), and a novel approach using the SAP depleting drug, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), which derives from Pepys’s research on systemic amyloidosis. SAP is significantly produced only in the liver and reaches the brain from the circulating blood. Within the brain SAP binds to both amyloid plaques and tangles and brain SAP content is invariably raised in Alzheimer’s disease. Importantly, in as yet unpublished studies, Pepys and colleagues have confirmed earlier reports that human SAP is neurotoxic in vitro and in vivo. Human SAP binds to some cerebral neurons, enters the cells, tracks to the nucleus and has adverse effects in vitro. Three different independent strains of human SAP transgenic mice all develop abnormalities of synaptic transmission as they age and also have increased numbers of apoptotic retinal ganglion cells. Pepys developed CPHPC, a new chemical entity, hexanoyl bis (D-proline), to target SAP in systemic amyloidosis. It rapidly and almost completely depletes circulating SAP for as long as the drug is administered. Neither CPHPC itself nor prolonged SAP depletion has produced any adverse effects in any animal or human receiving the drug. Importantly, CPHPC also inhibits SAP binding to neurons and prevents the development of neuronal and synaptic transmission abnormalities in human SAP transgenic mice. In an early proof of concept, 3 month study in five patients with Alzheimer’s disease, we have demonstrated that during administration of CPHPC, SAP becomes undetectable in the CSF. With funding from the UK National Institute of Health Research we are working towards a one year double blind, placebo controlled, phase II clinical trial of CPHPC in patients with Alzheimer’s disease. As part of this trial, the Dana Foundation award will support a study to explore synaptic plasticity, using transcranial magnetic stimulation of the motor cortex. This provides an in vivo correlate of the synaptic transmission abnormalities in mice with transgenic expression of human SAP which are prevented by long term SAP depletion with CPHPC.