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\"Computer Architectures is a collection of multidisciplinary historical works that unearth sites, concepts, and concerns that catalyzed the cross-contamination of computers and architecture in the mid-20th century. Actively constructing the common ground between design and computing, this collection addresses audiences working at the nexus of design, technology, and society, including historians and practitioners of design and architecture, science and technology scholars, and media studies scholars\"-- Provided by publisher.

Activity-dependent neuroprotective protein (ADNP), essential for brain formation, was discovered as a leading de novo mutated gene causing the autism-like ADNP syndrome. This syndrome is phenotypically characterized by global developmental delays, intellectual disabilities, speech impediments, and motor dysfunctions. The Adnp haploinsufficient mouse mimics the human ADNP syndrome in terms of synapse density and gene expression patterns, as well as in developmental, motor, and cognitive abilities. Peripheral ADNP was also discovered as a biomarker for Alzheimer’s disease and schizophrenia, with nasal administration of the ADNP snippet peptide NAP (enhancing endogenous ADNP activity) leading to partial cognitive and functional protection at the cellular, animal and clinical settings. Here, a novel formulation for effective delivery of NAP is provided with superior brain penetration capabilities. Also provided are methods for treating pertinent clinical implications such as autism, cognitive impairments, olfactory deficits, and muscle strength using the formulation in the Adnp haploinsufficient mouse. Results showed a dramatically specific increase in brain/body bioavailability with the new formulation, without breaching the blood brain barrier. Additional findings included improvements using daily intranasal treatments with NAP, at the behavioral and brain structural levels, diffusion tensor imaging (DTI), translatable to clinical practice. Significant effects on hippocampal and cerebral cortical expression of the presynaptic Slc17a7 gene encoding vesicular excitatory glutamate transporter 1 (VGLUT1) were observed at the RNA and immunohistochemical levels, explaining the DTI results. These findings tie for the first time a reduction in presynaptic glutamatergic synapses with the autism/Alzheimer’s/schizophrenia-linked ADNP deficiency coupled with amelioration by NAP (CP201).

Given our recent discovery of somatic mutations in autism spectrum disorder (ASD)/intellectual disability (ID) genes in postmortem aged Alzheimer’s disease brains correlating with increasing tauopathy, it is important to decipher if tauopathy is underlying brain imaging results of atrophy in ASD/ID children. We concentrated on activity-dependent neuroprotective protein (ADNP), a prevalent autism gene. The unique availability of multiple postmortem brain sections of a 7-year-old male, heterozygous for ADNP de novo mutation c.2244Adup/p.His559Glnfs*3 allowed exploration of tauopathy, reflecting on a general unexplored mechanism. The tested subject exhibited autism, fine motor delays, severe intellectual disability and seizures. The patient died after multiple organ failure following liver transplantation. To compare to other ADNP syndrome mutations, immortalized lymphoblastoid cell lines from three different patients (including ADNP p.Arg216*, p.Lys408Valfs*31, and p.Tyr719* heterozygous dominant mutations) and a control were subjected to RNA-seq. Immunohistochemistry, high-throughput gene expression profiles in numerous postmortem tissues followed. Comparisons to a control brain and to extensive datasets were used. Live cell imaging investigated Tau-microtubule interaction, protecting against tauopathy. Extensive child brain tauopathy paralleled by multiple gene expression changes was discovered. Tauopathy was explained by direct mutation effects on Tau-microtubule interaction and correction by the ADNP active snippet NAP. Significant pathway changes (empirical P value < 0.05) included over 100 genes encompassing neuroactive ligand–receptor and cytokine–cytokine receptor interaction, MAPK and calcium signaling, axon guidance and Wnt signaling pathways. Changes were also seen in steroid biosynthesis genes, suggesting sex differences. Selecting the most affected genes by the ADNP mutations for gene expression analysis, in multiple postmortem tissues, identified Tau (MAPT)-gene-related expression changes compared with extensive normal gene expression (RNA-seq) databases. ADNP showed relatively reduced expression in the ADNP syndrome cerebellum, which was also observed for 25 additional genes (representing >50% of the tested genes), including NLGN1, NLGN2, PAX6, SMARCA4 , and SNAP25 , converging on nervous system development and tauopathy. NAP provided protection against mutated ADNP disrupted Tau-microtubule association. In conclusion, tauopathy may explain brain-imaging findings in ADNP syndrome children and may provide a new direction for the development of tauopathy protecting drug candidates like NAP in ASD/ID.

Background : Exercise training induces beneficial effects on neurodegenerative diseases, and specifically on multiple sclerosis (MS) and it’s model experimental autoimmune encephalomyelitis (EAE). However, it is unclear whether exercise training exerts direct protective effects on the central nervous system (CNS), nor are the mechanisms of neuroprotection fully understood. In this study, we investigated the direct neuroprotective effects of high-intensity continuous training (HICT) against the development of autoimmune neuroinflammation and the role of resident microglia. Methods : We used the transfer EAE model to examine the direct effects of training on the CNS. Healthy mice performed HICT by treadmill running, followed by injection of encephalitogenic proteolipid (PLP)-reactive T-cells to induce EAE. EAE severity was assessed clinically and pathologically. Brain microglia from sedentary (SED) and HICT healthy mice, as well as 5-days post EAE induction (before the onset of disease), were analyzed ex vivo for reactive oxygen species (ROS) and nitric oxide (NO) formation, mRNA expression of M1/M2 markers and neurotrophic factors, and secretion of cytokines and chemokines. Results : Transfer of encephalitogenic T-cells into HICT mice resulted in milder EAE, compared to sedentary mice, as indicated by reduced clinical severity, attenuated T-cell, and neurotoxic macrophage/microglial infiltration, and reduced loss of myelin and axons. In healthy mice, HICT reduced the number of resident microglia without affecting their profile. Isolated microglia from HICT mice after transfer of encephalitogenic T-cells exhibited reduced ROS formation and released less IL-6 and monocyte chemoattractant protein (MCP) in response to PLP-stimulation. Conclusions : These findings point to the critical role of training intensity in neuroprotection. HICT protects the CNS against autoimmune neuroinflammation by reducing microglial-derived ROS formation, neurotoxicity, and pro-inflammatory responses involved in the propagation of autoimmune neuroinflammation.

Background Nerve growth factor (NGF) and its receptors, tropomyosin receptor kinase A (TrkA) and pan-neurotrophin receptor p75 (p75NTR), are known to play bidirectional roles between the immune and nervous system. There are only few studies with inconclusive results concerning the expression pattern and role of NGF, TrkA, and p75NTR (NGF system) under the neuroinflammatory conditions in multiple sclerosis (MS) and its mouse model, the experimental autoimmune encephalomyelitis (EAE). The aim of this study is to investigate the temporal expression in different cell types of NGF system in the central nervous system (CNS) during the EAE course. Methods EAE was induced in C57BL/6 mice 6–8 weeks old. CNS tissue samples were collected on specific time points: day 10 (D10), days 20–22 (acute phase), and day 50 (chronic phase), compared to controls. Real-time PCR, Western Blot, histochemistry, and immunofluorescence were performed throughout the disease course for the detection of the spatio-temporal expression of the NGF system. Results Our findings suggest that both NGF and its receptors, TrkA and p75NTR, are upregulated during acute and chronic phase of the EAE model in the inflammatory lesions in the spinal cord. NGF and its receptors were co-localized with NeuN + cells, GAP-43 + axons, GFAP + cells, Arginase1 + cells, and Mac3 + cells. Furthermore, TrkA and p75NTR were sparsely detected on CNPase + cells within the inflammatory lesion. Of high importance is our observation that despite EAE being a T-mediated disease, only NGF and p75NTR were shown to be expressed by B lymphocytes (B220 + cells) and no expression on T lymphocytes was noticed. Conclusion Our results indicate that the components of the NGF system are subjected to differential regulation during the EAE disease course. The expression pattern of NGF, TrkA, and p75NTR is described in detail, suggesting possible functional roles in neuroprotection, neuroregeneration, and remyelination by direct and indirect effects on the components of the immune system.

Accumulation of aberrant proteins and inclusion bodies are hallmarks in most neurodegenerative diseases. Consequently, these aggregates within neurons lead to toxic effects, overproduction of reactive oxygen species and oxidative stress. Autophagy is a significant intracellular mechanism that removes damaged organelles and misfolded proteins in order to maintain cell homeostasis. Excessive or insufficient autophagic activity in neurons leads to altered homeostasis and influences their survival rate, causing neurodegeneration. The review article provides an update of the role of autophagic process in representative chronic and acute neurodegenerative disorders.

Oxidative stress, particularly of mitochondrial origin, plays an important role in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) and other tauopathies. Controversies regarding the responses of tau phosphorylation state to various stimuli causing oxidative stress have been reported. Here we investigated the effect of 3-nitropropionic acid (3NP), a mitochondrial toxin which induces oxidative stress, on the tangle-pathology in our previously generated double mutant (E257T/P301S, DM) -Tau-tg mice and in WT-mice. We detected an increase in tangle pathology in the hippocampus and cortex of the DM-Tau-tg mice following exposure of the mice to the toxin, as well as generation of tangles in WT-mice. This increase was accompanied with alterations in the level of the glycogen synthase kinase 3β (GSK3β), the kinase which phosphorylates the tau protein, and in the phosphorylation state of this kinase. A response of microglial cells was noticed. These results point to the involvement of mitochondrial dysfunction in the development of the tangle-pathology and may suggest that interfering with mitochondrial dysfunction may have an anti-tangle therapeutic potential.

ABSTRACTStatin treatment has been associated with a reduced risk of Alzheimer disease and decreased amyloid deposition in mouse models. No animal studies have reported effects of statins on tau aggregates and neurofibrillary tangles (NFTs), the pathological hallmarks of Alzheimer disease that correlate with dementia. We investigated the effect of statins on NFTs in a transgenic mouse tauopathy model and found the following1) 1-month treatment with the blood-brain barrier-permeable agent simvastatin in normocholesterolemic aged mice significantly reduced the NFT burden and decreased lectin-positive microglia; 2) simvastatin significantly decreased NFTs and improved T-maze performance in young animals treated for 8 months; 3) treatment of hypercholesterolemic mice for 5 months with blood-brain barrier-impermeable atorvastatin markedly reduced the NFT burden and decreased lectin-positive microglia; 4) nonstatin cholesterol-lowering strategies showed a modest NFT decrease compared with statin treatment; and 5) there was a positive correlation between microglial and NFT burden (r = 0.8). Together, these results suggest that statins reduce NFT burden irrespective of blood-brain barrier permeability at both early and late ages in long- and short-term treatment paradigms and under normocholesterolemic and hypercholesterolemic conditions. The decrease in microglia, coupled with the limited effect of nonstatin cholesterol lowering, suggests that the anti-NFT effect of statins may be related to their anti-inflammatory and not necessarily to their cholesterol-lowering properties. Statins may provide therapy against NFTs in tauopathies, particularly when NFTs are the major neuropathologic component.

Background Nogo-A and its putative receptor NgR are considered to be among the inhibitors of axonal regeneration in the CNS. However, few studies so far have addressed the issue of local NgR complex multilateral localization within inflammation in an MS mouse model of autoimmune demyelination. Methods Chronic experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice. Analyses were performed on acute (days 18–22) and chronic (day 50) time points and compared to controls. The temporal and spatial expression of the Nogo receptor complex (NgR and coreceptors) was studied at the spinal cord using epifluorescent and confocal microscopy or real-time PCR. Data are expressed as cells/mm 2 , as mean % ± SEM, or as arbitrary units of integrated density. Results Animals developed a moderate to severe EAE without mortality, followed by a progressive, chronic clinical course. NgR complex spatial expression varied during the main time points of EAE. NgR with coreceptors LINGO-1 and TROY was increased in the spinal cord in the acute phase whereas LINGO-1 and p75 signal seemed to be dominant in the chronic phase, respectively. NgR was detected on gray matter NeuN + neurons of the spinal cord, within the white matter inflammatory foci (14.2 ± 4.3 % NgR + inflammatory cells), and found to be colocalized with GAP-43 + axonal growth cones while no β-TubIII + , SMI-32 + , or APP + axons were found as NgR + . Among the NgR + inflammatory cells, 75.6 ± 9.0 % were microglial/macrophages (lectin + ), 49.6 ± 14.2 % expressed CD68 (phagocytic ED1 + cells), and no cells were Mac-3 + . Of these macrophages/monocytes, only Arginase-1 + /NgR + but not iNOS + /NgR + were present in lesions both in acute and chronic phases. Conclusions Our data describe in detail the expression of the Nogo receptor complex within the autoimmune inflammatory foci and suggest a possible immune action for NgR apart from the established inhibitory one on axonal growth. Its expression by inflammatory macrophages/monocytes could signify a possible role of these cells on axonal guidance and clearance of the lesioned area during inflammatory demyelination.

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deficiency of the survival motor neuron (SMN) protein. Although SMA is a genetic disease, environmental factors contribute to disease progression. Common pathogen components such as lipopolysaccharides (LPS) are considered significant contributors to inflammation and have been associated with muscle atrophy, which is considered a hallmark of SMA. In this study, we used the SMNΔ7 experimental mouse model of SMA to scrutinize the effect of systemic LPS administration, a strong pro-inflammatory stimulus, on disease outcome. Systemic LPS administration promoted a reduction in SMN expression levels in CNS, peripheral lymphoid organs, and skeletal muscles. Moreover, peripheral tissues were more vulnerable to LPS-induced damage compared to CNS tissues. Furthermore, systemic LPS administration resulted in a profound increase in microglia and astrocytes with reactive phenotypes in the CNS of SMNΔ7 mice. In conclusion, we hereby show for the first time that systemic LPS administration, although it may not precipitate alterations in terms of deficits of motor functions in a mouse model of SMA, it may, however, lead to a reduction in the SMN protein expression levels in the skeletal muscles and the CNS, thus promoting synapse damage and glial cells’ reactive phenotype.