A number of experimental observations support a role for axonal transport defects in Alzheimer¹s disease (Morfini et al., 2002). Two recent papers reporting impaired axonal transport caused by presenilin mutations and Aβ protein, respectively, lend additional support to this hypothesis. Presenilin mutations increase GSK3β activity leading to abnormal kinesin phosphorylation and impaired axonal transport (Pigino et al., 2003; see also ARF live discussion). The molecular mechanism by which Aβ inhibits fast axonal transport (FAT) in neurons is not clear. According to results by Hiruma and coworkers in this study, Aβ-mediated inhibition of FAT involves actin polymerization and aggregation; however, the study does not present evidence of the molecular mechanism(s) that might lead to changes in microfilament polymerization. One possibility is that Aβ abnormally activates...  Read more

A number of experimental observations support a role for axonal transport defects in Alzheimer¹s disease (Morfini et al., 2002). Two recent papers reporting impaired axonal transport caused by presenilin mutations and Aβ protein, respectively, lend additional support to this hypothesis. Presenilin mutations increase GSK3β activity leading to abnormal kinesin phosphorylation and impaired axonal transport (Pigino et al., 2003; see also ARF live discussion). The molecular mechanism by which Aβ inhibits fast axonal transport (FAT) in neurons is not clear. According to results by Hiruma and coworkers in this study, Aβ-mediated inhibition of FAT involves actin polymerization and aggregation; however, the study does not present evidence of the molecular mechanism(s) that might lead to changes in microfilament polymerization. One possibility is that Aβ abnormally activates focal adhesion signals, resulting in misregulation of actin dynamics leading to impaired axonal transport and neuritic dystrophy (Grace and Busciglio, 2003). This hypothesis is supported by the presence of activated focal adhesion proteins in dystrophic neurites surrounding Aβ plaque cores in the Alzheimer's brain. Interestingly, we found in the same study that activation of focal adhesion signaling may also lead to a direct induction of MAP kinase and GSK3β, two kinases that appear to be involved in tau hyperphosphorylation, which in turn may lead to microtubule destabilization and impaired axonal transport (see ARF comment). In addition, other studies suggest that a direct accumulation of Aβ and APP metabolic derivatives in neuronal processes may be responsible for trafficking alterations (Bayer et al., 2001; Wirths et al., 2002). Collectively, these results indicate that Aβ may alter axonal transport in neurons in a number of different ways. Future studies directed to advance our understanding of the role of axonal transport defects in AD neuropathology are warranted.

View all comments by Jorge Busciglio

The study by Pigino et al. study elegantly highlights a possible mechanism by which Aβ oligomers can influence axonal transport. Though the validity of intracellular Aβ is debatable in the context of human AD pathology, Pigino et al. convincingly show that in a simple model-system of axonal transport, nanomolar levels of Aβ can influence transport; they also provide convincing evidence for the involvement of a specific signaling cascade in this process. The paper is a must-read!

View all comments by Subhojit Roy