Neverthe less, the evidence causally implicates CH25H in response to infection inflammation as a triggering factor for chol esterol mobilization, esterification, and foam cell forma tion. Outstanding questions are summarized in Table 2. Concluding remarks Brain versus body, why do some individuals develop AD, others ATH There are significant differences between brain this research and body, these could explain potential differences in the outcome of systemic infection and inflammation. First, the brain differs from the body in cholesterol metabolism. In addition to being a net exporter of chol esterol, the CNS produces a brain specific sterol, 24 OHC, known as cerebrosterol. The enzyme respon sible, CYP46A1, is predominantly expressed in the brain most highly in areas affected by AD and polymorphisms in the gene cytochrome P450, family 46, subfamily A, polypeptide 1, CYP46A1, have been associated with risk of AD development.

It is not known whether 24 OHC has specific immunoregu latory effects, but it is certainly plausible to suggest that that activity of CYP46 will impact upon the production and ef fects of 25 hydroxycholesterols, noting that 24,25 dihydroxycholesterol resolves to 24,25 epoxycholes terol, a further immunosterol with potent biological ef fects including inhibition Inhibitors,Modulators,Libraries of virus proliferation. Second, some infectious agents home selectively to the brain and propagate therein. Examples include encephal itis viruses, poliovirus, rabies virus, and different Inhibitors,Modulators,Libraries mem bers of the herpesvirus family.

It is possible AD reflects infection and inflammation in association with the cere brovasculature, whereas ATH is the result of infections propagating in the peripheral vasculature. Third, the brain immune system differs from that in other tissues. The brain contains its own specialized macrophage like cells, the microglia, that share Inhibitors,Modulators,Libraries with macrophages the properties of self renewal, mobility, cytokine and chemokine responsiveness, antigen pres entation, and phagocytosis, although the brain contains both typical macrophages and microglia. Brain microglia could potentially contribute to AD development, but the evidence is inconclusive. Fourth, microtubule associated protein Tau is particu larly abundant in CNS neurons, and AD is associated with intracellular aggregates of Tau. APOE3 binds avidly to Tau whereas APOE4 shows no Inhibitors,Modulators,Libraries significant bind ing.

This interaction may Inhibitors,Modulators,Libraries modulate AD development but only make a minor contribution to ATH. Causes, cures, and age dependence In both ATH and AD we see central involvement of vascular pathology, clinical association with common predisposing genes alleles, association with infection, disease enhancement by immune stimulation, the central role of bone marrow derived cells, principally macro phages, our the involvement of AB, drug overlap, and choles terol involvement.