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Aging and several neurodegenerative diseases bring about changes in the anatomy and physiology of the choroid plexus. The identification of specific membrane receptors that bind and internalize extracellular ligands has revolutionized the traditional roles of this tissue. Amyloid beta peptide (Aβ), the major constituent of the amyloid core of senile plaques in patients with Alzheimer's disease (AD) is known to contribute to disease neuropathology and progression. Recent emphasis on comorbidity of AD and a deficient clearance of Aβ across the blood-brain barrier and blood-cerebrospinal fluid barrier have highlighted the importance of brain Aβ clearance in AD. The megalin receptor has also been implicated in the pathogenesis of AD. Faulty Aβ clearance from the brain across the choroid plexus epithelium by megalin appears to mediate focal Aβ accumulation in AD. Patients with AD have reduced levels of megalin at the choroid plexus, which in turn seem to increase brain levels of Aβ through a decreased efflux of brain Aβ. Therapies that increase megalin expression at the choroid plexus could potentially control accumulation of brain Aβ. This review covers in depth the anatomy and function of the choroid plexus, focusing on the brain barrier at the choroid plexus, as it actively participates in Aβ clearance. In addition, we describe the role of the choroid plexus in brain functions, aging and AD, as well as the role of megalin in the process of Aβ clearance. Finally, we present current data on the use of choroid plexus cells to repair the damaged brain.

There is growing evidence that leptin is able to ameliorate Alzheimer's disease (AD)-like pathologies, including brain amyloid-β (Aβ) burden. In order to improve the therapeutic potential for AD, we generated a lentivirus vector expressing leptin protein in a self-inactivating HIV-1 vector (HIV-leptin), and delivered this by intra-cerebroventricular administration to APP/PS1 transgenic model of AD. Three months after intra-cerebroventricular administration of HIV-leptin, brain Aβ accumulation was reduced. By electron microscopy, we found that APP/PS1 mice exhibited deficits in synaptic density, which were partially rescued by HIV-leptin treatment. Synaptic deficits in APP/PS1 mice correlated with an enhancement of caspase-3 expression, and a reduction in synaptophysin levels in synaptosome preparations. Notably, HIV-leptin therapy reverted these dysfunctions. Moreover, leptin modulated neurite outgrowth in primary neuronal cultures, and rescued them from Aβ42-induced toxicity. All the above changes suggest that leptin may affect multiple aspects of the synaptic status, and correlate with behavioral improvements. Our data suggest that leptin gene delivery has a therapeutic potential for Aβ-targeted treatment of mouse model of AD.

The functional Val158Met polymorphism (rs4680) located at the gene that codes for the catechol-O-methyltransferase (COMT) has been extensively investigated in schizophrenia although current data are still controversial. Since COMT activity is sexually dimorphic, we carried out two independent studies in homogeneous samples of male and female Spanish schizophrenic patients. In males, we found an association between the homozygous Val genotype and the disorder, which resembled a recessive model (P = 0.022; odds ratio [OR] = 1.67). This Val homozygotes overrepresentation is produced at the expense of the heterozygous individuals decrease, whilst the Met homozygotes showed no differences when compared controls and patients. As a consequence, the heterozygous genotype in this sample had a protective effect (P = 0.03; OR = 0.65) and a strong deviation from Hardy-Weinberg equilibrium in male cases was observed (P = 0.006). In addition, a 2-SNP haplotype analysis (rs4818-Val158Met) confirmed there is an overrepresentation of the different homozygous Val genotypes in the male schizophrenic sample. Regarding females, we did not find any statistically significant association between COMT SNP and schizophrenia. In the light of this we suggest that the Val158Met SNP is involved in risk and protective genotypes for the vulnerability to schizophrenia in Spanish male population.

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