Alzheimer's Disease Neurodevelopment Converges with Neurodegeneration

dues, perhaps by a CNR-associated Src family protein Alzheimer’s disease (AD) is the most common senile tyrosine kinase. Phosphorylation of Dab somehow dementia in the elderly. The disease is characterized causes the migrating neuron to cease migrating, release behaviorally by global cognitive decline, and defined from its substratum, the radial glial cell, and begin to histologically by two distinguishing pathologies: amydifferentiate. This picture is supported by the observaloid plaques, which are extracellular deposits consisting tion that mutations in Dab or a double mutant in ApoER2 mainly of aggregated b-amyloid peptide, and neurofibriland VLDLR give phenotypes identical to that of Reelin lary tangles, which are intracellular deposits consisting mutants, and by biochemical analysis of Reelin signalpredominantly of hyperphosphorylated tau protein. A ing. Moreover, genetic ablation of Reelin or the ApoE central direction in efforts to understand AD has been to receptors eliminates Dab phosphorylation and leads to identify genetic mechanisms that predispose individuals dramatic upregulation of Dab levels. Together, these to developing the disease. Most notably, familial AD data suggest that Dab either mediates or regulates sigfrequently results from mutations in genes encoding the naling by Reelin receptors in cortical development. b-amyloid peptide precursor protein bPP or genes enCDK5 as a Downstream Element Controlling coding presenilins, which are responsible for processing Migration of Cortical Neurons of bPP. Also, specific alleles of Apolipoprotein E (ApoE) It is clear that Reelin, ApoER2/VLDLR, and Dab are reincrease the risk of developing sporadic forms of AD, quired for the transmembrane signaling that establishes and influence the age of onset of familial AD. However, the pattern of cortical neuron migration, but how the these discoveries have not yet provided a clear undersignal is propagated downstream of Dab is much less standing of the molecular mechanism of the disease, clear. One strong hint comes from the observation that nor have they revealed the nature of the connection mutations in the gene encoding the serine/threonine between its twin hallmarks, plaques and tangles. protein kinase CDK5, or in its activating subunit p35, Surprisingly, several of the genes and proteins associproduce defects in cortical neuron migration that resemated with AD have recently been found to play central ble those caused by loss of the Reelin signal (Chae et roles in early neural development, particularly neuronal al., 1997). Might CDK5/p35 therefore be a downstream migration and axon extension. Although the potential element in signaling by Reelin/ApoER2-VLDLR/Dab? significance of this observation has not escaped the Several lines of evidence are consistent with this conjecattention of investigators, no coherent picture has yet ture. In particular, the Abl protein tyrosine kinase, which emerged of the relationship between neurodevelopmen-