Showing papers by "Mark B. Pepys published in 2009"

Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component.

Abstract: New therapeutic approaches in Alzheimer's disease are urgently needed. The normal plasma protein, serum amyloid P component (SAP), is always present in cerebrospinal fluid (CSF) and in the pathognomonic lesions of Alzheimer's disease, cerebrovascular and intracerebral Abeta amyloid plaques and neurofibrillary tangles, as a result of its binding to amyloid fibrils and to paired helical filaments, respectively. SAP itself may also be directly neurocytotoxic. Here, in this unique study in Alzheimer's disease of the bis(d-proline) compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), we observed depletion of circulating SAP and also remarkable, almost complete, disappearance of SAP from the CSF. We demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. We have also solved the structure of SAP complexed with phosphothreonine, its likely ligand on hyperphosphorylated tau protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neurodegenerative diseases.

C-Reactive Protein and Coronary Disease: Is There a Causal Link?

Abstract: Inflammation has been proposed as a contributor to different stages in the pathogenesis of coronary heart disease (CHD), including the lifelong process of atherogenesis, the acute atherothrombotic event that causes ischemic necrosis in acute myocardial infarction, and the myocardial damage after ischemia.1,2 C-reactive protein (CRP), an acute-phase plasma protein synthesized by the liver, is the most extensively studied systemic marker of inflammation.3 Since the original report of an association between modest increases in baseline circulating CRP and subsequent cardiovascular outcomes in patients with unstable angina at the initial examination,4,5 CRP has been the focus of intense investigation. Measurement of CRP has been advocated as a means of improving cardiovascular risk prediction.6 Because CRP binds to low-density lipoprotein (LDL)7 and is present in atherosclerotic plaques,8 there is also considerable interest in whether CRP may play a direct causal role in CHD (and, by implication, could be an important therapeutic target for disease prevention). As discussed below, the evidence relating to this hypothesis has been derived from several different routes of enquiry, including observational epidemiology, human genetic studies, experimental and animal models, and randomized clinical trials of statins. Collectively, several recent findings, such as those in this issue of Circulation from Koike et al9 on human CRP transgenic rabbits, have reduced the likelihood that CRP itself is a major causal mediator in CHD. In this editorial, we briefly summarize the strengths and limitations of the available data, with an emphasis on the recent major findings. Article see p 2088 In regard to observational epidemiology, the first population-based prospective study of CRP concentration and CHD risk appeared in 1996.10 By 2009, >50 additional such studies had been reported.11–14 The rapid appearance of epidemiological studies on CRP has been facilitated greatly by the relative stability …

A molecular correlate of clinicopathology in transthyretin amyloidosis.

Abstract: The mechanisms responsible for amyloid deposition at different times and in different organs, even in individuals with the same amyloidogenic mutation, are not known. The demonstration, in hereditary systemic transthyretin Val30Met amyloidosis, that such differences are consistently associated with amyloid fibrils composed of different length transthyretin fragments sheds new light on this question and will open the way to further informative studies.