Human glial fibrillary acidic protein-delta (GFAP-delta) is a GFAP protein isoform that is encoded by an alternative splice variant of the GFAP-gene. As a result, GFAP-delta protein differs from the predominant splice form, GFAP-alpha, by its C-terminal protein sequence. In this study, we show that GFAP-delta protein is not expressed by all GFAP-expressing astrocytes but specifically by a subpopulation located in the subpial zone of the cerebral cortex, the subgranular zone of the hippocampus, and, most intensely, by a ribbon of astrocytes following the ependymal layer of the cerebral ventricles. Therefore, at least in the sub ventricular zone (SVZ), GFAP-delta specifically marks the population of astrocytes that contain the neural stem cells in the adult human brain. Interestingly, the SVZ astrocytes actively splice GFAP-delta transcripts, in contrast to astrocytes adjacent to this layer. Furthermore, we show that GFAP-delta protein, unlike GFAP-alpha, is not upregulated in astrogliosis. Our data therefore indicate a different functional role for GFAP-delta in astrocyte physiology. Finally, transfection studies showed that GFAP-delta protein expression has a negative effect on GFAP filament formation, and therefore could be important for modulating intermediate filament cytoskeletal properties, possibly facilitating astrocyte motility. Further studies on GFAP-delta and the cells that express it are important for gaining insights into its function during differentiation, migration and during health and disease.

Loss of neurons in neurodegenerative diseases is usually preceded by the accumulation of protein deposits that contain components of the ubiquitin/proteasome system. Affected neurons in Alzheimer's disease often accumulate UBB+1, a mutant ubiquitin carrying a 19–amino acid C-terminal extension generated by a transcriptional dinucleotide deletion. Here we show that UBB+1 is a potent inhibitor of ubiquitin-dependent proteolysis in neuronal cells, and that this inhibitory activity correlates with induction of cell cycle arrest. Surprisingly, UBB+1 is recognized as a ubiquitin fusion degradation (UFD) proteasome substrate and ubiquitinated at Lys29 and Lys48. Full blockade of proteolysis requires both ubiquitination sites. Moreover, the inhibitory effect was enhanced by the introduction of multiple UFD signals. Our findings suggest that the inhibitory activity of UBB+1 may be an important determinant of neurotoxicity and contribute to an environment that favors the accumulation of misfolded proteins.

A disturbed sleep-wake rhythm is common in Alzheimer disease (AD) patients and correlated with decreased melatonin levels and a disrupted circadian melatonin rhythm. Melatonin levels in the cerebrospinal fluid are decreased during the progression of AD neuropathology (as determined by the Braak stages), already in cognitively intact subjects with the earliest AD neuropathology (Braak stages I-II) (preclinical AD). To investigate the molecular mechanisms behind the decreased melatonin levels, we measured monoamines and mRNA levels of enzymes of the melatonin synthesis and its noradrenergic regulation in pineal glands from 18 controls, 33 preclinical AD subjects, and 25 definite AD patients. Pineal melatonin levels were highly correlated with cerebrospinal fluid melatonin levels. The circadian melatonin rhythm disappeared because of decreased nocturnal melatonin levels in both the preclinical AD and AD patients. Also the circadian rhythm of beta(1)-adrenergic receptor mRNA disappeared in both patient groups. The precursor of melatonin, serotonin was stepwise depleted during the course of AD, as indicated by the up-regulated monoamine oxidase A mRNA and activity (5-hydroxyindoleacetic acid:serotonin ratio). We conclude that a dysfunction of noradrenergic regulation and the depletion of serotonin by increased monoamine oxidase A result in the loss of melatonin rhythm already in preclinical AD.

Deposition of the amyloid-beta peptide is a pathological hallmark of Alzheimer's disease. A high-throughput functional genomics screen identified G protein-coupled receptor 3 (GPR3), a constitutively active orphan G protein-coupled receptor, as a modulator of amyloid-beta production. Overexpression of GPR3 stimulated amyloid-beta production, whereas genetic ablation of GPR3 prevented accumulation of the amyloid-beta peptide in vitro and in an Alzheimer's disease mouse model. GPR3 expression led to increased formation and cell-surface localization of the mature gamma-secretase complex in the absence of an effect on Notch processing. GPR3 is highly expressed in areas of the normal human brain implicated in Alzheimer's disease and is elevated in the sporadic Alzheimer's disease brain. Thus, GPR3 represents a potential therapeutic target for the treatment of Alzheimer's disease.