DENN/MADD/IG20 alternative splicing changes and cell death in Alzheimer's disease.

The potential effects of alternative splicing of death-domain expressing genes and neuronal death have not been determined in Alzheimer's disease (AD). We analyzed DENN/MADD/IG20 (DMI), the complex of four splice variants. IG20 is known to be involved in cell death and the DENN/MADD splice variant (DM-SV) in cell survival in non-neural systems. DENN/MADD (DM) and DENN/MADD splice variant 2 were also included. Using SH-SY5Y human neuroblastoma cultures exposed to high concentrations of oligomeric Aß peptides (oAß) as a model for neuronal death, there was initially an increased ratio of DM-SV to IG20 (DM-SV/IG20) and knockdown of DMI SVs including DM-SV with antisense DNA then increased cell death. Cultures transfected with small interfering RNAs (siRNAs) specific to subsets of DMI SVs but sparing DM-SV increased the DM-SV/IG20 ratio resulting in a reduction of cell death in the presence of oAß. Effects on cell survival of DM and DM SV2, the other two SVs expressed in the CNS, are less clear. Compared to normal controls, alternative splicing changes in the CNS of AD patients during disease progression resulted in altered ratios of all of the SVs in a pattern over an extended time that mirrored that of the cultures, and coincided with the accumulation of endogenous, dimeric Aß (dAß). Thus, DM-SV may be required for neuronal survival by protecting against oAß neurotoxicity, and IG20 may contribute to selective neuronal vulnerability in AD.

Exercise elevates dopamine D2 receptor in a mouse model of Parkinson's disease: in vivo imaging with [¹8F]fallypride.

The purpose of the current study was to examine changes in dopamine D2 receptor (DA-D2R) expression within the basal ganglia of MPTP mice subjected to intensive treadmill exercise. Using Western immunoblotting analysis of synaptoneurosomes and in vivo positron emission tomography (PET) imaging employing the DA-D2R specific ligand [¹8F]fallypride, we found that high intensity treadmill exercise led to an increase in striatal DA-D2R expression that was most pronounced in MPTP compared to saline treated mice. Exercise-induced changes in the DA-D2R in the dopamine-depleted basal ganglia are consistent with the potential role of this receptor in modulating medium spiny neurons (MSNs) function and behavioral recovery. Importantly, findings from this study support the rationale for using PET imaging with [¹8F]fallypride to examine DA-D2R changes in individuals with Parkinson's Disease (PD) undergoing high-intensity treadmill training.

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 (oAbeta). To identify immediate molecular targets downstream of oAbeta 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 Abeta (dAbeta). 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 alpha-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 dAbeta.

The dominant role of solvent in the sequestering of bile salts by hydrophobic cationic polymeric resins.

The binding behavior of sodium cholate, a trihydroxy hydrophobic bile salt, by a polyacrylamide resin with N,N,N-trimethylammonium dodecyl chloride (QPDA12) pendant group was determined with varying buffer conditions and in the presence of 1,2-propanediol as a solvent perturbant. Binding constants extracted from the fit of the binding isotherms to the Langmuir equation were obtained at several temperatures. The temperature dependence of the binding behavior indicated that binding, in comparison with that of the dihydroxy chenodeoxycholate, was weaker due to a smaller positive entropic change, despite a lowered enthalpic barrier. Enthalpy-entropy compensation with a compensation temperature of 285-290 K, characteristic of processes involving water, was found to encompass both the cholate and chenodeoxycholate data under a wide variety of conditions. Previous studies with sodium chenodeoxycholate determined that loss of hydrophobic hydration within the resin dominated the thermodynamics of the binding process, but the observations with sodium cholate revealed that solvent liberation about the bile salt is also a contributor.