title: Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Aβ amyloid deposits in vivo.
abstract: Human amyloid deposits always contain the normal plasma protein serum amyloid P component (SAP), owing to its avid but reversible binding to all amyloid fibrils, including the amyloid β (Aβ) fibrils in the cerebral parenchyma plaques and cerebrovascular amyloid deposits of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). SAP promotes amyloid fibril formation in vitro, contributes to persistence of amyloid in vivo and is also itself directly toxic to cerebral neurons. We therefore developed (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), a drug that removes SAP from the blood, and thereby also from the cerebrospinal fluid (CSF), in patients with AD. Here we report that, after introduction of transgenic human SAP expression in the TASTPM double transgenic mouse model of AD, all the amyloid deposits contained human SAP. Depletion of circulating human SAP by CPHPC administration in these mice removed all detectable human SAP from both the intracerebral and cerebrovascular amyloid. The demonstration that removal of SAP from the blood and CSF also removes it from these amyloid deposits crucially validates the strategy of the forthcoming 'Depletion of serum amyloid P component in Alzheimer's disease (DESPIAD)' clinical trial of CPHPC. The results also strongly support clinical testing of CPHPC in patients with CAA.
authors: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK.
authors: Raya
authors: http://orcid.org/0000-0002-9174-8924
authors: R
authors: Al-Shawi
authors: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK.
authors: Glenys A
authors: http://orcid.org/0000-0002-4645-5671
authors: GA
authors: Tennent
authors: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK.
authors: David J
authors: DJ
authors: Millar
authors: Division of Neuropathology and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors: Angela
authors: A
authors: Richard-Londt
authors: Division of Neuropathology and Department of Neurodegenerative Disease, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors: Sebastian
authors: http://orcid.org/0000-0002-9821-0342
authors: S
authors: Brandner
authors: Stroke Research Group, Department of Brain Repair and Rehabilitation, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK.
authors: David J
authors: http://orcid.org/0000-0003-2074-1861
authors: DJ
authors: Werring
authors: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK.
authors: J Paul
authors: http://orcid.org/0000-0002-5007-6674
authors: JP
authors: Simons
authors: Wolfson Drug Discovery Unit, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, Royal Free Campus, University College London, Rowland Hill Street, London NW3 2PF, UK m.pepys@ucl.ac.uk.
authors: Mark B
authors: http://orcid.org/0000-0003-2614-3248
authors: MB
authors: Pepys
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000188:drug therapy / Q000378:metabolism*; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000683:Serum Amyloid P-Component
keywords: Alzheimer's disease; Aβ amyloid; CPHPC; cerebral amyloid angiopathy; serum amyloid P component