Early markers of microglial activation and neural distress

Description

Microglia activation is thought to be a driving force of neurodegeneration, but confirmatory evidence is still elusive and biomarkers have not been identified. In particular, the possible relationship between cause and consequence for microglia activation and pathological landmarks, such as neuronal cell death and demyelination in EAE and cerebral ischemia, is still disputed. In cooperation with partners 4 and 6 and associate Partner 15, partner 11 intends to study two mouse models of diseases in which microglia activation and neurodegeneration interact, to try to identify a “very early” marker for microglia activation as compared to neural distress markers. EAE is considered to be a primary neuroinflammatory disease, whereas cerebral ischemia is recognized as a primary neurodegenerative disorder. However, we know that neurodegeneration is an early event in EAE, such as microglial activation in cerebral ischemia. Partner 11 will focus on the cortex and spinal cord to study microglial activation, astroglial reaction and early distress/neurodegeneration events in EAE at different stages of the disease and in stroke models. The selection of potential early markers of microglial activation will be guided by the results obtained by partners 4 and 9. Microglia activation will be investigated by multiplex RT-PCR (SABiosciences) and by cytokine assays based on the Luminex xMAP platform. When appropriate, selective cell populations, as identified by immunohistochemistry of activation markers, will be microdissected and collected for mRNA analysis. Results will be compared with those obtained through sorting of microglial cells by partner 4. Partner 11 will investigated neuronal distress in tissue sections by using quantitative morphometry of several markers for glutamate transmission, calcium homeostasis and mitochondrial function. Candidate markers will also be investigated in plasma and cerebrospinal fluid (CSF) in a cooperative effort with partner 10.

Publications

• Balducci C, Mehdawy B, Mare L, Giuliani A, Lorenzini L, Sivilia S, Giardino L, Calzà L, Lanzillotta A, Sarnico I, Pizzi M, Usiello A, Viscomi AR, Ottonello S, Villetti G, Imbimbo BP, Nisticò G, Forloni G, Nisticò R (2011) The ?-secretase modulator CHF5074 restores memory and hippocampal synaptic plasticity in plaque-free Tg2576 mice. J Alzheimers Dis 24: 799-816.
• Lanzillotta A, Sarnico I, Benarese M, Branca C, Baiguera C, Hutter-Paier B, Windisch M, Spano P, Imbimbo BP, Pizzi M (2011) The ?-secretase modulator CHF5074 reduces the accumulation of native hyperphosphorylated tau in a transgenic mouse model of Alzheimer's disease. J Mol Neurosci 45: 22-31.

Tasks and methodology

• EAE and stroke models
• Determination of gene expression by quantitative PCR and cytokine assays based on the
• Luminex xMAP platform
• Microdissection, quantitative morphometry

Planned secondment

University of Brescia, Investigation of microglial polarization, 9 month