**3. Reelin in the adult brain**

(VLDLR) and the ApolipoproteinE receptor 2 (ApoER2) [37]. The binding of Reelin to its re‐ ceptor induce the phosphorylation of the adapter protein mDab1 on tyrosine residues [38]. mDab1 phosphorylation lead eventually to the modulation of cytoskeleton effectors mole‐

**Figure 1.** Reelin signaling pathway in normal brain and its impairment in AD brains. The panel A show the intracellular events triggered by the binding of Reelin to its canonical membrane receptors, ApoER2 and VLDLR. mDab1 protein is spe‐ cifically phosphorylated at tyrosine residues, which concomitantly with the activation of PI3K, regulate actin and microtu‐ bule dynamic behavior. LIMK-mediated phosphorylation of cofilin and the Akt inhibitory phosphorylation of GSK-3β are essential to this regulation. On the other hand, in AD brains, diminished Reelin expression and its aggregation in amyloidlike deposits, induce impairment in its signaling pathway (represented by gray lines). Decreased Reelin signaling triggers the dephosphorylation of cofilin, promoting the formation of actin-rods. On the other hand, the activation of GSK-3β and

CDK-5, lead to hyperphosphorylation of tau protein inducing its aggregation into PHFs (panel B).

cules such as MAP1B and cofilin [23].

42 Understanding Alzheimer's Disease

Although Reelin function is mainly related to neurodevelopment, several recently studies assign roles in the adult brain, such as the development of dendrites and dendritic spines [36], modulation of synaptogenesis [39], modulation of synaptic plasticity [40-43] and neuro‐ transmitter release [44]. The mechanism by which Reelin can modulate the synaptic trans‐ mission is not fully elucidated. Currently it is strongly suggested that Reelin acting through its canonical signaling pathway facilitates the phosphorylation of NR2A and NR2B subunits of the NMDA receptor, favoring the calcium influx into the postsynaptic neuron.

This intracellular calcium increase causes the insertion of the GluR1 subunit of AMPA re‐ ceptors, allowing the phosphorylation and nuclear translocation of CREB [45]. CREB phos‐ phorylation is required to elicit the formation of dendritic spines. In addition, Reelin reduces the number of silent synapses, facilitating the exchange of subunit NR2B by NR2A of NMDA receptor [46]. Therefore, Reelin modulates synaptic plasticity events involved in learning and memory processes in adults. Consistently with a role for Reelin in the control of neurotransmission, *reeler* mice show diminished expression of presynaptic (SNARE, SNAP-25) [44] and postsynaptic (PSD-95, PTEN) markers [43]. These defects cause failures in the release of neurotransmitters, impairing synaptic transmission.
