Benway, TA; (2017) Investigation of SAP, NPTX1 and their interaction on synaptic function and microglia activity and their possible role in Alzheimer's disease. Doctoral thesis , UCL (University College London).

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Abstract

The pentraxins comprise of a family of proteins that exist in the brain to modulate synaptic formation and plasticity, and in the periphery as part of the immune response. Both the peripheral pentraxin serum amyloid-P component (SAP) and the neuronal pentraxin 1 (NPTX1) have been implicated in Alzheimer’s disease (AD) and show up-regulation in AD brains. SAP is always found on amyloid plaques and is linked to amyloid fibril stability, while NPTX1 is present in dystrophic neurons in plaques and can mediate some of the effects of amyloid-beta (Aβ). Under conditions of blood-brain barrier compromise, SAP can also enter the brain and is capable of exerting effects on synaptic transmission. Results from the current study show that SAP is capable of forming complexes with the neuronal pentraxins. Specifically, SAP can bind with NPTX1, NPTX2 and NPTXR when co-overexpressed in 293T cells. To investigate the effects that this complex may be having in the brain, SAP and NPTX1 were applied separately or simultaneously to primary neurons and to organotypics slices. To evaluate post-synaptic effects, spine density after SAP and/or NPTX1 application was examined. NPTX1 application resulted in decreased spine density, but this effect was prevented by SAP. A similar blocking effect of NPTX1 by SAP was found in the microglia counts from organotypic cultures, where NPTX1 alone resulted in decreased microglia and NPTX1+SAP showed a reduced deficit. Application of both SAP and NPTX1 resulted in a decrease in the proportion of activated microglia, whereas the application of either pentraxin alone was not found to affect levels of activation. Therefore, while SAP alone has no effect, it can block the effect of NPTX1 in decreasing microglial numbers, and contribute to decreased activation levels when co-applied with NPTX1. These results suggest that when SAP enters the brain it may be capable of exerting effects on synaptic transmission and immune response in the CNS via an interaction with the neuronal pentraxins.

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