Transcriptome Analysis of Synaptoneurosomes Identifies Neuroplasticity Genes Overexpressed in Incipient Alzheimer's Disease

In Alzheimer's disease (AD), early deficits in learning and memory are a consequence of synaptic modification induced by toxic beta-amyloid oligomers (oAβ). To identify immediate molecular targets downstream of oAβ binding, we prepared synaptoneurosomes from prefrontal cortex of control and incipient AD (IAD) patients, and isolated mRNAs for comparison of gene expression. This novel approach concentrates synaptic mRNA, thereby increasing the ratio of synaptic to somal mRNA and allowing discrimination of expression changes in synaptically localized genes. In IAD patients, global measures of cognition declined with increasing levels of dimeric Aβ (dAβ). These patients also showed increased expression of neuroplasticity related genes, many encoding 3′UTR consensus sequences that regulate translation in the synapse. An increase in mRNA encoding the GluR2 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) was paralleled by elevated expression of the corresponding protein in IAD. These results imply a functional impact on synaptic transmission as GluR2, if inserted, maintains the receptors in a low conductance state. Some overexpressed genes may induce early deficits in cognition and others compensatory mechanisms, providing targets for intervention to moderate the response to dAβ

Manipulation of the nerve growth factor network in prostate cancer

Autocrine and paracrine events regulated by nerve growth factor (NGF) and relevant receptors (low- and high affinity; p75 neurotrophin receptor [p75NTR] and TrkA, respectively) seem to play a significant role in prostate carcinogenesis. Studies reveal that p75NTR is both a tumor suppressor of growth and a metastasis suppressor of human prostate cancer cells. Furthermore, p75NTR is progressively lost during prostate carcinogenesis. An imbalance between p75NTR and tropomyosin receptor kinase A (TrkA)-mediated signals may be involved in the progression of prostate cancer through increased proliferation and reduced apoptosis. The antiproliferative and apoptotic effects of GnRH analogs in prostate cancer cells may be mediated by altering the TrkA:p75NTR NGF receptor ratio. Administration of NGF induces a reversion of the and androgen-independent/androgen receptor-negative prostate cancer cell lines to a less malignant phenotype. Finally, Trk inhibition is a novel, attractive and rational approach for prostate cancer therapy. This review unravels the NGF 'circuitry' in prostate cancinogenesis for relevant pharmacologic manipulation to lead to the development of novel therapeutic agent. © 2007 Informa UK Ltd

Genetic variability in the insulin signalling pathway may contribute to the risk of late onset Alzheimer's disease

Objective: To test the hypothesis that polymorphic variation in insulin signalling genes may underlie the shared risk of dysfunctional insulin signalling and late onset Alzheimer's disease (AD). The p85α subunit of phosphatidyl inositol 3 kinase (PIK3R1) and the regulatory subunit 3 of protein phosphatase 1 (PPP1R3) were selected as candidate genes because both encode key proteins involved in insulin signalling and because polymorphisms in these genes have been previously implicated in insulin resistance or type II diabetes. Methods: Analysis of the Met326Ile PIK3R1 and the Asp905Tyr PPP1R3 polymorphisms in 202 patients with late onset AD and 160 or 170 age matched normal subjects. Results: Logistic regression analysis using the recessive genetic model showed significant differences in genotype and allelic frequencies between the AD group and normal controls (genotypes: odds ratio (OR) 2.09, 95% confidence interval (CI) 1.17 to 3.74, p = 0.01; alleles: OR 1.99, 95% CI 1.17 to 3.40, p = 0.01) for the Met326Ile PIK3R1 polymorphism that were female specific. Additionally, in the dominant genetic model a marginally significant association in genotype frequencies between the Asp905Tyr PPP1R3 polymorphism and AD was observed (genotypes: OR 1.85, 95% CI 1.03 to 3.30, p = 0.04; alleles: OR 1.68, 95% CI 0.98 to 2.88, p = 0.06). Both polymorphisms were tested for their interactions with sex and the presence of the apolipoprotein E ε4 allele. Conclusions: The results support the hypothesis for a common genetic aetiology predisposing to insulin resistance and AD