Benway, T

Cummings, D

Edwards, F

Foster, E

Lashley, T

Liu, W

Murray, CE

Richardson, J

Salih, D

Yasvoina, M

UCL Discovery

Title: The pentraxin family regulates neuronal and microglial function in the CNS and is disrupted in phenotypes associated with Alzheimer’s disease.  Authors: Cummings, D.M.*1, Benway, T.A.* 1, Foster, E. 1, Liu, W. 1, Yasvoina, M.V. 1, Lashley, T.2, Murray, C.2, Richardson, J.C.3, Edwards, F.A.†1, Salih, D.A.† 1  Affiliations: 1Dept of Neuroscience, Physiology and Pharmacology, UCL, Gower St, London, UK 2Queen Square Brain Bank, London 3Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK *Joint first authors, †Joint corresponding authors  Introduction: At synapses, neuronal pentraxin 1 (NPTX1), NPTX2 and NPTX receptor form pentamers, playing a role in plasticity by clustering AMPA receptors (O'Brien et al. 2002 J.Neurosci. 22:4487-98). NPTX1 also mediates amyloidβ-induced neurite degeneration and NPTX2 regulates inflammation, a process dysregulated in Alzheimer’s disease (AD) (Abad et al. 2006 J.Neurosci. 26:12735-47). The liver also secretes pentraxins, e.g. serum amyloid P component (SAP) that may enter the brain as the blood-brain-barrier breaks down during AD.  Materials and Methods: Models: Transgenic mice (human APPswe+PSEN1M146V, or TauP301L). Human AD brain sections. Hippocampal organotypic slice cultures from wild type mice. Patch clamp recording in organotypic slices. Immunohistochemistry: antibodies against neuronal pentraxins and SAP; Aβ1-40 and Aβ1-42 for amyloid pathology; AIF1 and CD68 for microglial number and activation.   Results: We show that NPTX1 and SAP stain amyloid plaques, both in brain sections from AD patients and APP+PSEN1 mice, indicating that both pentraxins interact with plaques. Interestingly, SAP can form complexes with NPTX family members when they are co-expressed in HEK293 cells, suggesting that SAP could interact with neuronal pentraxins. Application of nanomolar concentrations of each of the human pentraxins over 7 days reduced paired-pulse ratios at CA3-CA1 synapses. This indicates an increase in glutamate release probability, similar to that observed in APPswe+PSEN1M146V mice (Cummings et al. 2015 Brain 138:1992-2004). Furthermore, our www.mouseac.org database indicates changes in expression of neuronal pentraxins at different ages in mouse models (Matarin et al. 2015 Cell Reports 10:633-44).  Finally, we show that NPTX receptor is expressed in BV2 mouse microglial cells and that adding NPTX1 or SAP to organotypic hippocampal slices decreases the number of microglia.  Conclusions: Both neuronal and peripheral pentraxins have effects on release of glutamate and can interact with AD plaques, possibly modulating the plaque-related microglial response. The peripheral pentraxin SAP, when it enters the brain, can form complexes with the neuronal pentraxins. 

The pentraxin family regulates neuronal and microglial function in the CNS and is disrupted in phenotypes associated with Alzheimer’s disease

http://discovery.ucl.ac.uk/1495960/1/Benway_ARUK%20Manchester%20Mar%202016%20v4.pdf

The pentraxin family regulates neuronal and microglial function in the CNS and is disrupted in phenotypes associated with Alzheimer’s disease

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