The Beta-Amyloid Protein of Alzheimer’s Disease: Communication Breakdown by Modifying the Neuronal Cytoskeleton

Figure 3

Model of Aβ-mediated neurite outgrowth inhibition. Aβ (oligomeric) activates the small GTPase, RhoA, which inhibits the proneurite outgrowth GTPase Rac1. RhoA-GTP activates Rho Kinase (ROCK II) to effect microfilament rearrangement and also potentiate microtubule disassembly. Microtubule disassembly occurs when ROCK II directly phosphorylates CRMP-2 at the Thr555 position preventing the association of CRMP-2 with tubulin heterodimers, thereby affecting neurite outgrowth inhibition. Neurite outgrowth is further impeded by CRMP-2 phosphorylation since this prevents the microtubule motor protein, kinesin, to associate with CRMP-2 and transport growth-related vesicular cargo, such as BDNF, antergradely to the distal end of the neurite. It is demonstrated that CRMP-2 is also phosphorylated by GSK-3β and Cdk-5. (A) Studies have demonstrated that GSK-3β activity can also regulate the processing of APP resulting in the production of Aβ, which in turn can further increase GSK-3β activity through PI3K inhibition, illustrating as a potential feedback loop. (B) Additionally, it has been suggested that Cdk5 may phosphorylate presenilin-1 at Thr354 destabilising its carboxy-terminal fragment, leading to increased APP processing.