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.
Highlights
The amyloid fibrils which are deposited as the pathognomonic intracerebral amyloid plaques and cerebrovascular amyloid deposits in Alzheimer’s disease (AD) are composed of the amyloid b (Ab) peptide [1]
In order to validate our methods for subsequent application to studies in human serum amyloid P component (SAP) transgenic mice, we examined brain sections from nine confirmed sporadic cerebral amyloid angiopathy (CAA) patients using Congo red staining for amyloid and immunohistochemical staining of adjacent sections for SAP and Ab
We have shown that administration of the SAP depleting drug, carboxypyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), produces sustained depletion of plasma SAP for as long as the drug is administered [29] and that depletion of circulating SAP leads to complete disappearance of SAP from the cerebrospinal fluid (CSF) in patients with AD [30]
Summary
The amyloid fibrils which are deposited as the pathognomonic intracerebral amyloid plaques and cerebrovascular amyloid deposits in Alzheimer’s disease (AD) are composed of the Ab peptide [1]. Ab is derived by sequential proteolytic cleavage of the amyloid precursor protein (APP) first by b-secretase [2], and subsequently by the g-secretase complex, of which the presenilin proteins (PSEN 1, PSEN 2) are the catalytic subunits [3]. Autosomal dominant hereditary AD is caused by mutations in, or duplication of, the APP gene and by mutations in the PSEN 1, PSEN 2 genes [4]. The Ab amyloid in sporadic cerebral amyloid angiopathy (CAA) clearly causes the structural disruption which results in vascular dysfunction and cerebral haemorrhage, just as the amyloid deposits in the tissues cause disease in systemic amyloidosis [6].
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