Amyloid P immunoreactivity precedes C4d deposition on extracellular neurofibrillary tangles

Extracellular neurofibrillary tangles (eNFTs) are the insoluble cytoskeletal debris left behind when neurons with intracellular neurofibrillary tangles (iNFTs) die. Reactive microglia and reactive astrocytes gather around eNFTs. Many inflammatory proteins are deposited in their vicinity, including activated components of the classical complement pathway. Agents which are potential activators of the pathway include beta-amyloid protein (A beta) and amyloid P (AP), since these in vitro activators have been reported to be associated with both senile plaques (SPs) and eNFTs. To investigate the apparent order in which these proteins are deposited, we studied by immunohistochemistry the relative association of AP, A beta, and the classical complement protein C4d with eNFTs in Alzheimer's disease (AD), parkinsonism-dementia complex of Guam (lytico-bodig, LB), and elderly non-demented cases. In normal elderly cases with mild tangle development, most but not all eNFTs were AP positive. Substantially fewer eNFTs were C4d positive, and in two of the three cases no eNFTs were A beta positive. In AD and mild LB cases with more extensive tangle development, a high portion of eNFTs were AP positive, and most of them were C4d positive. Only a few were A beta positive. In severe LB cases, with dense tangle development, almost all eNFTs were AP and C4d positive, and a significant number were also A beta positive. AP seems to be deposited early in eNFT exposure and could therefore be a potential activator of the complement pathway, while A beta deposition occurs relatively late in the process, and is therefore unlikely to be responsible.