Autism, Schizophrenia and Alzheimer’s Disease : a common thread from neuropeptides to brain regulating genes

Our original cloning of the gene coding for vasoactive intestinal peptide (VIP) (Bodner, Fridkin & Gozes, 1985), led to the identification of VIP’s involvement in synapse formation and neuroprotection, through our discoveries of activity-dependent neurotrophic factor (ADNF) (Brenneman & Gozes, 1996) and activity- dependent neuroprotective protein (ADNP) (Bassan et al., 1999; Zamostiano et al., 2001). To precisely delineate VIP and ADNP activities in the whole animal, we established transgenic animals, showing that manipulating VIP content impacts cognition in the mouse (Gozes et al., 1993). As for mouse ADNP, complete knockout results in severe neuronal tube closure defects and embryonic death at the time of neural tube closure (Pinhasov et al., 2003). ADNP haploinsufficient mice survive and show cognitive and social deficiencies, with pathologies resembling autism (Malishkevich et al., 2015) and Alzheimer’s disease (Vulih-Shultzman et al., 2007). Delineating the mechanism of action of ADNP, we discovered binding to the SWI/SNF chromatin remodeling complex and heterochromatin protein 1 alpha, and direct interaction with specific gene promoters (e.g. the major risk gene for Alzheimer’s disease, apolipoprotein E) (Mandel & Gozes, 2007; Mandel, Rechavi & Gozes, 2007). We have further discovered interactions with proteins associated with RNA splicing (Schirer et al., 2014), as well as with proteins regulating translation, like eukaryotic initiation factor 4E (Eif4e) (Malishkevich et al., 2015). In the cell cytoplasm, ADNP further interacts with the autophagy mechanism, binding to microtubule associated protein 1 light chain 3 (LC3) (Merenlender-Wagner et al., 2015) and to microtubule end binding proteins (EBs) (Oz et al., 2014).peer-reviewe

Glucose-targeted niosomes deliver vasoactive intestinal peptide (VIP) to the brain

The aim of this study was to evaluate glucose-bearing niosomes as a brain targeted delivery system for the vasoactive intestinal peptide (VIP). To this end, VIP/125I-VIP-loaded glucose-bearing niosomes were intravenously injected to mice. Brain uptake was determined by measuring the radioactivity of 125I-labeled VIP using gamma-counting, after intravenous administration of VIP in solution or encapsulated in glucose-bearing niosomes or in control niosomes. VIP integrity was assessed by reversed-phase HPLC analysis of brain extracts. Distribution of 125I-VIP derived radioactivity was examined from serial brain slices. HPLC analysis confirmed the presence of intact VIP in brain after administration of VIP-loaded niosomes, but not after administration of VIP solution. Encapsulation within glucose-bearing niosomes mainly allowed a significantly higher VIP brain uptake compared to control niosomes (up to 86%, 5min after treatment). Brain distribution of intact VIP after injection of glucose-bearing niosomes, indicated that radioactivity was preferentially located in the posterior and the anterior parts of the brain, whereas it was homogeneously distributed in the whole brain after the administration of control vesicles. In conclusion, this novel vesicular formulation of VIP delivers intact VIP to particular brain regions in mice. Glucose-bearing vesicles might be therefore a novel tool to deliver drugs across the blood-brain barrier (BBB)

RGS2 expression predicts amyloid-β sensitivity, MCI and Alzheimer's disease: genome-wide transcriptomic profiling and bioinformatics data mining

Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-β (Aβ) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aβ in AD pathology have been raised as Aβ is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to Aβ neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aβ plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to Aβ. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P=0.0085) in LCLs from healthy individuals exhibiting high vs low Aβ sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P=0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients' cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, Aβ sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics

Tau and Caspase 3 as Targets for Neuroprotection

The peptide drug candidate NAP (davunetide) has demonstrated protective effects in various in vivo and in vitro models of neurodegeneration. NAP was shown to reduce tau hyperphosphorylation as well as to prevent caspase-3 activation and cytochrome-3 release from mitochondria, both characteristic of apoptotic cell death. Recent studies suggest that caspases may play a role in tau pathology. The purpose of this study was to evaluate the effect of NAP on tau hyperphosphorylation and caspase activity in the same biological system. Our experimental setup used primary neuronal cultures subjected to oxygen-glucose deprivation (OGD), with and without NAP or caspase inhibitor. Cell viability was assessed by measuring mitochondrial activity (MTS assay), and immunoblots were used for analyzing protein level. It was shown that apoptosis was responsible for all cell death occurring following ischemia, and NAP treatment showed a concentration-dependent protection from cell death. Ischemia caused an increase in the levels of active caspase-3 and hyperphosphorylated tau, both of which were prevented by either NAP or caspase-inhibitor treatment. Our data suggest that, in this model system, caspase activation may be an upstream event to tau hyperphosphorylation, although additional studies will be required to fully elucidate the cascade of events

Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking

© Voelzmann et al.The mechanisms regulating synapse numbers during development and ageing are essential for normal brain function and closely linked to brain disorders including dementias. Using Drosophila, we demonstrate roles of the microtubule-associated protein Tau in regulating synapse numbers, thus unravelling an important cellular requirement of normal Tau. In this context, we find that Tau displays a strong functional overlap with microtubule-binding spectraplakins, establishing new links between two different neurodegenerative factors. Tau and the spectraplakin Short Stop act upstream of a three-step regulatory cascade ensuring adequate delivery of synaptic proteins. This cascade involves microtubule stability as the initial trigger, JNK signalling as the central mediator, and kinesin-3 mediated axonal transport as the key effector. This cascade acts during development (synapse formation) and ageing (synapse maintenance) alike. Therefore, our findings suggest novel explanations for intellectual disability in Tau deficient individuals, as well as early synapse loss in dementias including Alzheimer’s disease