Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin-containing protein (VCP), the underlying disease mechanism remains elusive. Like IBMPFD, neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. Neurofibromin, the protein encoded by the NF1 gene, has been shown to regulate synaptogenesis. Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. Certain mutations identified in IBMPFD and NF1 patients reduced the interaction between VCP and neurofibromin and impaired spinogenesis. The functions of neurofibromin and VCP in spinogenesis were shown to correlate with the learning disability and dementia phenotypes seen in patients with IBMPFD. Consistent with the previous finding that treatment with a statin rescues behavioral defects in Nf1 +/-mice and providing further support for our hypothesis that there is crosstalk between neurofibromin and VCP, statin exposure neutralized the effect of VCP knockdown on spinogenesis in cultured hippocampal neurons. The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.

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Polyalthia longifolia var. pendula is used as an antipyretic agent in indigenous systems of medicine. Microglia-mediated inflammation plays an important role in the pathway leading to neuronal cell death in a number of neurodegenerative diseases. The aim of this study was to investigate the effects of 6-hydroxycleroda-3,13-dien-15,16-olide (PL3) extracted from Polyalthia longifolia var. pendula on lipopolysaccharide(LPS)-induced inflammation in microglia-like HAPI cells and primary microglia cultures. In microglia-neuron co-cultures, LPS decreased the cell viability of neuroblastoma SH-SY5Y cells. LPS-induced cell death was attenuated by the NOS inhibitor, L-NAME, the COX-2 inhibitor, NS-398 or the NADPH oxidase inhibitor, DPI, respectively. In LPS-treated microglia cells, PL3 decreased the expression of iNOS, COX-2, gp91 (phox), and NF- kappaBp65, the degradation of I kappaB alpha, and the production of NO, PGE (2), iROS, and TNF- alpha. PL3 also enhanced the expression of HO-1, a cytoprotective and anti-inflammatory enzyme. Moreover, PL3 reduced LPS-activated microglia-induced cell death. The present results suggest that PL3 inhibits microglia-mediated inflammation and inflammation-related neuronal cell death. Therefore, PL3 has potential use for the treatment of inflammation-related neurodegenerative diseases.

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