Hypothetical model how dysfunctional Reelin-mediated signaling may induce pathological aging. In the course of normal aging, Reelin accumulates in the extracellular matrix either as monomers, dimers, or oligomers and/or cleaved fragments, which are efficiently cleared by activated astrocytes and microglia [39, 108]. Long-term imbalances in immune modulators including elevated levels of pro-inflammatory cytokines in old subjects increase the expression of metalloproteinases, resulting in aberrant cleavage of extracellular Reelin and production of an excess of Reelin fragments. While N-terminal fragments might preferentially aggregate in concert with proteolytic APP fragments [105], the central fragments are expected to compete with full-length Reelin homodimers for the available receptors to inhibit Reelin downstream signaling. Dysfunctional Reelin signaling is expected to promote not only amyloidogenic APP processing [7, 19, 111] including the production of N-APP, and Tau hyperphosphorylation [16, 24, 25, 137], it likely also impairs synaptic plasticity [28, 45, 52] via the strong reduction of several Reelin-mediated downstream signaling cascades required for proper neuronal functioning. NFT = Neurofibrillary tangles. Thin arrows represent downregulation; thick arrows indicate an up-regulation compared to the normal signaling pathways described during development and adult synaptic functions.
