Michael J. Mullan, M.D.

CD40, Microglial Activation and Neuronal Amyloid Precursor Protein Processing

The central pathologies in AD include cerebral amyloidosis, neurofibrillary tangles and widespread inflammatory changes in some rare genetic cases these features are triggered by mutations in the APP resulting in alterations in Abeta, which result in its early cerebral accumulation. These observations have led to the popular hypothesis that all cases of AD are triggered by accumulation of cerebral amyloid. In this hypothesis the other features of AD are thought to be a result of this accumulation including inflammation and hyperphosphorylation of tau leading to neurofibrillary tangles. Molecular interventions are thus frequently targeted towards the manipulation of APP processing away from AD production, or towards the reduction or prevention of the reactive inflammatory processes or (more rarely) towards the prevention of accumulation of aberrant tau isoforms. Therapeutic interventions in any of these areas hold promise for the prevention of the disease and several such interventions are underway experimentally and clinically.

We have shown that in vitro and in vivo models of APP processing, inflammation and tau hyperphosphorylation benefit from an absence of CD40L, the cognate ligand of CD40 As the effects of either genetic interference or antibody capture of CD40L results in marked reduction of amyloid burden, microgliosis, cerebral TNF-a levels and tau hyperphosphorylation in the brains of transgenic models of AD it would be important to know how these effects occur. For instance, understanding how CD40L can influence APP processing may open up more generic ways to avoid amyloidogenic processing of APP. Using a simple in vitro paradigm we hope to identify the steps between CD40L treatment and influence on APP processing in neurons and to understand the link between pro-inflammatory responses in microglia andAD/CD40L stimulation.