Current Alzheimer Research (v.13, #9)

Meet Our Editorial Board Member by Hermona Soreq (951-951).

Molecular Basis of Familial and Sporadic Alzheimer's Disease by Jolanta Dorszewska, Michal Prendecki, Anna Oczkowska, Mateusz Dezor, Wojciech Kozubski (952-963).
Alzheimer's disease (AD) is a multifactorial disease with genetic (70%) and environmental (30%) causes. Among the genetic factors are genes associated with a family history of the disease (familial AD, FAD) and sporadic AD (SAD). The genes: APP (amyloid precursor protein), PSEN1 (Presenilin 1) and PSEN2 (Presenilin 2) are responsible for the presence of FAD. The APOE gene is responsible for the sporadic form of the disease. Other molecular factors related to the immunological cause (TREM2) of the disease are a disorder of the lipid (ABCA1, ABCA7) or biothiol (MTHFD1) metabolism and of the transport of metabolites (BIN1). Currently, it is believed that APOE is a risk factor for both SAD and late-onset FAD.
The pathomechanism of AD is most commonly explained as based on the amyloid cascade theory. This theory is related to the FAD, although there are reports indicating the probability of its occurrence in the SAD. It seems that the excessive deposition of ?-amyloid (A?) peptides and intracellular neurofibrillary tangles of tau protein hyperphosphorylated forms contribute to the damage of both DNA and RNA. Furthermore, it is believed that RNA-interference can affect both the level of pathological proteins (A?, tau protein) and the onset and progress of AD.
It seems that a complete understanding of both FAD and SAD pathogenesis may contribute to the search for earlier clinical diagnosis and to an understanding of later occurrence of the disease, which may help modify its course and affect more effective therapy of this incurable neurological disease.

Substance P and Alzheimer's Disease: Emerging Novel Roles by Cinzia Severini, Carla Petrella, Pietro Calissano (964-972).
Alzheimer's disease (AD) is an irreversible neurodegenerative disease, clinically characterized by progressive impairments of memory and cognition. The hallmarks of AD are neurofibrillary tangles, mainly constituted by altered phosphorylated and truncated portions of tau protein, and the abnormal extracellular deposition of neurotoxic beta amyloid (Aβ) peptides, derived from the proteolytic processing of amyloid precursor protein (APP). According to the amyloid hypothesis, Aβ is considered to be linked to the selective neurodegeneration seen in AD. Recent evidence points to an increase in voltage-gated potassium (Kv) channel currents in the etiology of Aβ-induced neuronal apoptosis.
Substance P (SP) is an 11-aa neuropeptide, member of the tachykinin family, broadly distributed in the Central Nervous System where it acts as a neurotransmitter, neuromodulator, and neurotrophic factor. This peptide may play an important role in neurodegenerative disorders, since reduced levels of SP were found in brain areas and spinal fluid of AD patients. In addition to its neuroprotective properties, it was recently demonstrated that SP is able to stimulate non-amyloidogenic APP processing, thereby reducing the possibility of generation of toxic Aβ peptides in the brain. Recent studies, using in vitro and in vivo models, have also shown that the neuroprotective role of SP against Aβ could be related to its ability of modulate Kv channel currents.
In this review, we briefly summarized the current findings on the neurotrophic and neuroprotective effects of SP, providing information about its anti-amyloidogenic and anti-Aβ toxicity role.

Lipid Raft Alterations in Aged-Associated Neuropathologies by Raquel Marin, Noemí Fabelo, Cecilia Fernández-Echevarría, Ana Canerina-Amaro, Deiene Rodríguez-Barreto, David Quinto-Alemany, Fátima Mesa-Herrera, Mario Díaz (973-984).
Lipid rafts are membrane microdomains particularly enriched in cholesterol, sphingolipids and saturated fatty acids. These microstructures play a key role in a plethora of mechanisms involved in cell signaling, synapsis, cell-cell communication and cell survival. In the last years, increasing evidence indicate that lipid rafts may be altered in age-related neuropathologies, such as Alzheimer's disease and Parkinson disease even at asymptomatic stages. In particular, important changes in raft lipid composition are observed with the progression of these diseases, then inducing alterations in their physicochemical properties. Furthermore, these phenomena contribute to neuropathological events related to amyloidogenesis, aberrant protein aggregation and toxic cell signalling. In this review, we discuss some relevant data on the age-related molecular changes occurring in lipid rafts since the first stages of these neurodegenerative diseases. Further characterization of specific parameters associated with alterations of these microdomains may provide potential tools of diagnosis and prediction of these neuropathologies.

The BET-Bromodomain Inhibitor JQ1 Reduces Inflammation and Tau Phosphorylation at Ser396 in the Brain of the 3xTg Model of Alzheimer's Disease by Marco Magistri, Dmitry Velmeshev, Madina Makhmutova, Prutha Patel, Gregory C. Sartor, Claude-Henry Volmar, Claes Wahlestedt, Mohammad Ali Faghihi (985-995).
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation. Objective: The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown. Method: Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid ?. Results: JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice. Conclusion: Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.

Alzheimer's disease (AD) is currently one of the most studied neurodegenerative disorders in humans. First reported in 1907, the disease has a familial form which represents approximately 5% of cases, while the remaining, sporadic cases are of multifactorial etiology. The disease progression of the latter form has specific pathological and functional characteristics, which have unknown etiology. Several authors have proposed a viral etiology for AD, while others implicate many neurotropic infectious agents. This review compares research findings regarding pathways and effects of neuropathological viruses with the pathways and effects involved in the progression of AD. The similarities are striking and provide a compelling argument for a pathogen-based etiology of AD.

Misoprostol Reverse Hippocampal Neuron Cyclooxygenase-2 Downstream Signaling Imbalance in Aluminum-Overload Rats by Yuanxin Guo, Wenjuan Lei, Jianfeng Wang, Xinyue Hu, Yuling Wei, Chaonan Ji, Junqing Yang (1006-1016).
Although COX-2 inhibition in animal models of neurodegenerative diseases has shown neuroprotection, recent studies have revealed some serious side effects (ulcers, bleeding, fatal cerebrovascular diseases etc.) and the limited benefits of COX-2 inhibitors. A more focused approach is necessary to explore the therapeutic effect of the COX downstream signaling pathway in neurological research. The aim of this study was to explore the alterations of the PGES-PGE2-EP signal pathway and the effect of misoprostol on neurodegeneration by chronic aluminum-overload in rats. Adult rats were treated by intragastric administration of aluminum gluconate. The PGE2 content and expression of PGES and EPs in the hippocampi of rats were detected using ELISA, q-PCR and Western blot analysis, respectively. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in the rat hippocampi were also detected. The misoprostol treatment dose-dependently improved spatial learning and memory function as well as healing after hippocampal neuron damage induced by chronic aluminum-overload in rats. Meanwhile, the administration of misoprostol resulted in a decrease in the PGE2 level and down-regulation of the mPGES-1, EP2 and EP4 expression levels, while there was a dosedependent up-regulation of EP3 expression. These results suggest that misoprostol possesses a neuroprotective property, and the mechanism involves affecting the EP3 level and reducing the endogenous production of PGE2 through a negative feedback mechanism, increasing the EP3 expression level, decreasing the EP2 and EP4 expression levels, and rebuilding the mPGES-1-PGE2-EP1-4 signal pathway balance. In this way, misoprostol has a counteractive effect on oxidant stress and inflammation in the central nervous system. The PGES-PGE2-EPs signaling pathway is a potential therapeutic strategy for treating neurodegeneration in patients.

Rhein-Huprine Derivatives Reduce Cognitive Impairment, Synaptic Failure and Amyloid Pathology in A?PPswe/PS-1 Mice of Different Ages by Felipe G. Serrano, Cheril Tapia-Rojas, Francisco J. Carvajal, Pedro Cisternas, Elisabet Viayna, Irene Sola, Diego Munoz-Torrero, Nibaldo C. Inestrosa (1017-1029).
Alzheimer's disease (AD) is a neurodegenerative disorder in which the amyloid-? (A?) peptide plays a key role in synaptic impairment and memory decline associated with neuronal dysfunction and intra-neuronal accumulation of hyperphosphorylated tau protein. Two novel enantiopure rhein-huprine hybrids ((+)-1 and (-)-1) exhibit potent inhibitory effects against human acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE-1 and both A? and tau antiaggregation activity in vitro and reduction on the amyloid precursor protein (APP) processing in vivo. Interestingly, in this work, we observed beneficial effects with both (+)- and (-)-1 in the reversion of the neuropathology presented in the A?PPswe/PS-1 Alzheimer's model, including a reduction in the A? levels, tau phosphorylation and memory impairment with both treatments. Also, in young transgenic mice that present early symptoms of synaptic failure and memory loss, we found a protection of cognitive functions, including long-term potentiation (LTP) and a reduction of the neuro-inflammation by both (+)- and (-)-1. Furthermore, animals with an advanced disease (11month-old) present an exacerbate neurodegeneration that is reversed only with the dextrorotatory enantiomer. These studies indicated that rhein-huprine derivatives with multiple properties might have interesting therapeutic potential for AD.

Altered Arginine Metabolism in Cells Transfected with Human Wild-Type Beta Amyloid Precursor Protein (?APP) by Henryk J||ko, Anna Wilkaniec, Magdalena Cie|lik, Wojciech Hilgier, Magdalena G|ssowska, Walter J. Lukiw, Agata Adamczyk (1030-1039).
Alterations of enzymes linked to arginine metabolism have been recently implicated in Alzheimer's disease (AD). Despite strong association of arginine changes with nitric oxide (NO) pathway, the impact of amyloid ? (A?) peptides on arginine degradation and re-synthesis is unknown. In the present study we compared expression levels of arginases (ARG1, ARG2), neuronal, endothelial and inducible NO synthase isoforms (NNOS, ENOS, INOS), enzymes that metabolize arginine or resynthesize it from citrulline and the levels of corresponding amino acids in rat pheochromocytoma (PC12) cells overexpressing human A? precursor protein (APPwt cells). Moreover, we investigated the changes in miRNAs responsible for modulation of arginine metabolism in AD brains. Real-time PCR analysis revealed in APPwt cells significant decreases of ARG1 and ARG2 which are responsible for lysing arginine into ornithine and urea; this reduction was followed by significantly lower enzyme activity. NNOS and ENOS mRNAs were elevated in APPwt cells while iNOS was undetectable in both cell lines. The expression of argininosuccinate synthase (ASS) that metabolizes citrulline was down-regulated without changes in argininosuccinate lyase (ASL). Ornithine decarboxylase (ODC), which decarboxylates ornithine to form putrescine was also reduced. Arginine, the substrate for both arginases and NOS, was unchanged in APPwt cells. However, citrulline concentration was significantly higher. Elevated miRNA-9 and miRNA-128a found in AD brain tissues might modulate the expression of ASS and NOS, respectively. Our results indicate that A? affects arginine metabolism and this influence might have important role in the pathomechanism of AD.

Decreased Myelinated Fibers in the Hippocampal Dentate Gyrus of the Tg2576 Mouse Model of Alzheimer's Disease by Wei Lu, Shu Yang, Lei Zhang, Lin Chen, Feng-Lei Chao, Yan-min Luo, Qian Xiao, Heng-Wei Gu, Rong Jiang, Yong Tang (1040-1047).
Alzheimer's disease (AD), the most common cause of dementia in the elderly, is characterized by deficits in cognition and memory. Although amyloid-? (A?) accumulation is known to be the earliest pathological event that triggers subsequent neurodegeneration, how A? accumulation causes behavioral deficits remains incompletely understood. In this study, using the Morris water maze test, ELISA and stereological methods, we examined spatial learning and memory performance, the soluble A? concentration and the myelination of fibers in the hippocampus of 4-, 6-, 8- and 10-month-old Tg2576 AD model mice. Our results showed that spatial learning and memory performance was significantly impaired in the Tg2576 mice compared to the wild type (WT) controls and that the myelinated fiber length in the hippocampal dentate gyrus (DG) was markedly decreased from 0.33 ± 0.03 km in the WT controls to 0.17 ± 0.02 km in the Tg2576 mice at 10 months of age. However, the concentrations of soluble A?40 and A?42 were significantly increased as early as 4-6 months of age. The decreased myelinated fiber length in the DG may contribute to the spatial learning and memory deficits of Tg2576 mice. Therefore, we suggest that the significant accumulation of soluble A? may serve as a preclinical biomarker for AD diagnosis and that protecting myelinated fibers may represent a novel strategy for delaying the progression of early-stage AD.

APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice by Meng Zhou, Tianwen Huang, Nicole Collins, Jing Zhang, Hui Shen, Xiaoman Dai, Naian Xiao, Xilin Wu, Zhen Wei, Jason York, Lanyan Lin, Yuangui Zhu, Mary Jo LaDu, Xiaochun Chen (1048-1055).
APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), particularly associated with increased levels of amyloid-β (Aβ) and amyloid deposition. However, it remains unclear whether APOE4 is associated with greater tau phosphorylation and neurofibrillary tangle formation, a hallmark of AD leading to structural disruption of the neuronal cytoskeleton. The current study used 3 and 7 month old EFAD mice, which express human APOE and over-express specifically human Aβ42 via 5 familial-AD (FAD) mutations, to investigate APOE genotype-specific effects on site-specific tau phosphorylation. The results reveal that AD-like site-specific tau phosphorylation was increased in E4FAD mice, accompanied by disrupted cortical neuronal morphology, compared to E3FAD mice. Further analysis demonstrated that the levels of CDK5, its regulatory subunits (p35 and p25) and calpain (including calpain1 and calpain2), but not GSK3?, were significantly increased in E4FAD mice compared to E3FAD mice. These results suggest that the APOE4 genotype contributes to increased site-specific tau phosphorylation via activation of the calpain-CDK5 signaling pathway.

Inflammation, Oxidation, Caloric Expenditure and Cognitive Impairment in Brazilian Elderly Assisted at Primary Care by Guilherme M. Nogueira, Carla H.A. Schwanke, Vera E. Closs, Bruna Luz, Rafael N. Moresco, Etiane Tatsch, Guilherme V. Bochi, Joao F.D. de Moraes, Camila B. Jacondino, Irenio Gomes, Maria G.V. Gottlieb (1056-1063).
Cognitive impairment (CI) has a multifactorial etiology. Some studies have suggested that inflammatory, oxidative and antioxidant status and physical activity are associated with CI. However, the evidence on this subject is still controversial. The goal of this study was to verify the association of caloric expenditure by physical activity, oxidative, antioxidant power and inflammatory biomarkers with CI in older adults. We performed a cross-sectional study of 424 elderly (224 with normal cognitive function and 200 with CI) patients from the Family Health Strategy in Porto Alegre, Rio Grande do Sul, Brazil. The variables investigated were sociodemographic, biochemical, inflammatory (hs-CRP, IL-6), oxidative (TBARS, AOPP), antioxidant power (FRAP) biomarkers, energy expenditure, and cognitive function. The instruments used were the Minnesota Leisure Time Physical Activity Questionnaire + Compendium of Physical Activities, classification of energy costs of human physical activities (for physical activity evaluation and measurement of energy expenditure in METs), and a battery of neuropsychiatric instruments (for cognitive ability assessment). We found statistically significant differences only with respect to HDL-c and age (higher averages in the CI group; P<0.05). We observed no differences between the groups with respect to biochemical, inflammatory, oxidative and FRAP biomarkers or caloric expenditure. Logistic regression showed that HDL-c (OR=1.02 [IC=95%; 1.01-1.04]; P=0.011), and age (OR=1.05 [IC=95%; 1.02-1.08]; P=0.004) are independent factors associated with CI. Our results suggest that the biochemical (except HDL-c), inflammatory, oxidative, and FRAP biomarkers investigated and caloric expenditure are not associated with CI in the elderly assisted at primary care.