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The significance of neuroinflammation in understanding Alzheimer's disease

Several pathways are involved in Ab removal and the proportion of Ab that is removed may be different depending on the conditions in a given brain area (Saido, 2003; Oshima et al., 2006). The ﬁrst pathway is proteolytic degeneration by Ab-degrading enzymes such as neprisylin, the insulin-degrading enzyme (IDE) and plasmin (Qiu et al., 1998; Melchor et al., 2003; Iwata et  al.,  2005). A second  pathway  is  the  uptake  by astrocytes  and  microglia  and  subsequently  intracellular degradation. The third pathway is drainage of the Ab from the brain by a carrier-mediated transport system into the cerebrospinal ﬂuid  and  blood  or  by  passive  diffusion  or transport  of  the  interstitial  ﬂuid  via  the  Virchow-Robin space (Zlokovic,  2004;  Bateman  et  al.,  2006).

Increases in Ab production can explain the small percentage of early onset cases of familial AD bearing inherited mutations in APP or the presenilins 1 or 2 genes but similar increases in production have not been found in sporadic AD in spite of elevated levels  of  Ab  in  the  brain.