Two members of the family of low-density lipoprotein receptors (i.e., very 
low-density lipoprotein [VLDL] receptor and apolipoprotein E [apoE] type 2 
receptor) are expressed in brain, where they bind and transduce reelin, a 
secreted glycoprotein that shares structural analogies with extracellular matrix 
proteins. In the developing fetal brain, reelin-signal transduction is critical 
for the correct positioning of neurons and the formation of appropriate synaptic 
connections, whereas in the mature brain, reelin participates in the mediation 
of experience-dependent synaptic plasticity. An important "downstream" 
consequence of the reelin-signal transduction cascade is inhibition of the 
phosphorylation of tau, a protein that regulates microtubule assembly and 
stability. Importantly, hyperphosphorylated tau comprises the paired helical 
filament, whose pathological deposition as neurofibrillary tangles is implicated 
in Alzheimer's disease; hyperphosphorylated tau is also implicated in the 
pathogenesis of other neurodegenerative disorders. Isoforms of apoE may affect 
the binding of reelin to its cell surface receptors and, thereby, influence tau 
phosphorylation, whereas insulin, insulin-like growth factor-1, and the lithium 
ion have actions within the cell at the level of the specific tyrosine kinases 
involved in the phosphorylation of tau. These data support the exploration of 
pharmacotherapeutic interventions designed to prevent or reduce the burden of 
hyperphosphorylated tau. Impaired reelin-signal transduction due to an actual 
deficiency of reelin expression may occur in at least some patients with 
psychotic disorders, especially schizophrenia; conceivably, hyperphosphorylation 
of tau would result from deficient transduction of reelin in schizophrenia. 
Schizophrenia has been conceptualized as a neurodevelopmental disorder of 
impaired synaptic "connectivity", whose consequence does not become fully 
apparent until late adolescence or early adulthood. In summary, 
hyperphosphorylation of tau may be an underlying point of pathological 
convergence for several neuropsychiatric disorders, and prevention of tau 
hyperphosphorylation may be an important therapeutic target.