Journal of Alzheimer's Disease - Volume 56, issue 3

Authors: Lin, Tian-Syuan | Tsai, Han-Jung | Lee, Chih-Han | Song, Yan-Qing | Huang, Rih-Sheng | Hsieh-Li, Hsiu-Mei | Liang, Mei-Chih | Lin, Yenshou

Article Type: Research Article

Abstract: The presence of amyloid-β (Aβ) plaque and tau protein hyperphosphorylation in brain tissue is the pathological hallmark of Alzheimer’s disease (AD). At least some Aβ neurotoxicity is caused by the presence of excess glutamate that has been induced by Aβ accumulation. Memantine is currently the only NMDA receptor inhibitor approved for treating moderate-to-severe AD patients. We utilized primary cortical neurons and DiBAC4(3), a slow-response voltage sensitive fluorescence dye, to create a novel system for screening herbal medicines that allows the identification of pure compounds able to ameliorate Aβ-induced abnormal depolarization. The intensity of DiBAC4(3) fluorescence was increased when primary neurons were stimulated …by Aβ; furthermore, pre-treatment with memantine abolished this change. Using this system, we identified six crude extracts made from herbal medicines that effectively alleviated this Aβ-induced abnormal depolarization. Among these herbal medicines, one pure compound, baicalein, which was known to be present in Scutellaria baricalensi s and is known to improve memory using an AD mouse model, was identified by our assay. However, the compound’s molecular mechanism remained unknown. We found that baicalein, in addition to inhibiting Aβ-induced depolarization, possibly functions as an antagonist of AMPA and NMDA receptors. Taken together, we have established a system/platform to identify herbal medicines that ameliorate Aβ-induced depolarization of neurons. Equally important, baicalein is a candidate drug with great potential for the treatment of AD patients. Show more

Keywords: Alzheimer’s disease, amyloid-β, baicalein, DiBAC4(3), glutamate receptors, memantine

DOI: 10.3233/JAD-160898

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 959-976, 2017

Authors: Gomez-Ramos, Alberto | Picher, Angel J. | García, Esther | Garrido, Patricia | Hernandez, Felix | Soriano, Eduardo | Avila, Jesús

Article Type: Research Article

Abstract: Next-generation sequencing techniques and genome-wide association study analyses have provided a huge amount of data, thereby enabling the identification of DNA variations and mutations related to disease pathogenesis. New techniques and software tools have been developed to improve the accuracy and reliability of this identification. Most of these tools have been designed to discover and validate single nucleotide variants (SNVs). However, in addition to germ-line mutations, human tissues bear genomic mosaicism, which implies that somatic events are present only in low percentages of cells within a given tissue, thereby hindering the validation of these variations using standard genetic tools. Here …we propose a new method to validate some of these somatic mutations. We combine a recently developed software with a method that cuts DNA by using restriction enzymes at the sites of the variation. The non-cleaved molecules, which bear the SNV, can then be amplified and sequenced using Sanger’s technique. This procedure, which allows the detection of alternative alleles present in as few as 10% of cells, could be of value for the identification and validation of low frequency somatic events in a variety of tissues and diseases. Show more

Keywords: Alzheimer’s disease, identification of nucleotide variations, Sanger sequencing, somatic mutations, Virmid software

DOI: 10.3233/JAD-161053

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 977-990, 2017

Authors: Salza, Romain | Lethias, Claire | Ricard-Blum, Sylvie

Article Type: Research Article

Abstract: The goals of this work were i) to identify the interactions of amyloid-β (Aβ)42 under monomeric, oligomeric, and fibrillar forms with the extracellular matrix (ECM) and receptors, ii) to determine the influence of Aβ42 supramolecular organization on these interactions, and iii) to identify the molecular functions, biological processes, and pathways targeted by Aβ42 in the ECM. The ECM and cell surface partners of Aβ42 and its supramolecular forms were identified with protein and glycosaminoglycan (GAG) arrays (81 molecules in triplicate) probed by surface plasmon resonance imaging. The number of partners of Aβ42 increased upon its …multimerization, ranging from 4 for the peptide up to 53 for the fibrillar aggregates. The peptide interacted only with ECM proteins but their percentage among Aβ42 partners decreased upon multimerization. Aβ42 and its supramolecular forms recognized different molecular features on their partners, and the partners of Aβ42 fibrillar forms were enriched in laminin IV-A, N-terminal, and EGF-like domains. Aβ42 oligomerization triggered interactions with receptors, whereas Aβ42 fibrillogenesis promoted binding to GAGs, proteoglycans, enzymes, and growth factors and the ability to interact with perineuronal nets. Fibril aggregation bind to further membrane proteins including tumor endothelial marker-8, syndecan-4, and discoidin-domain receptor-2. The partners of the Aβ42 supramolecular forms are enriched in proteins contributing to cell growth and/or maintenance, involved in integrin cell surface interactions and expressed in kidney cancer, preadipocytes, and dentin. In conclusion, the supramolecular assembly of Aβ42 governs its ability to interact in vitro with ECM proteins, remodeling and crosslinking ECM enzymes, proteoglycans, and receptors. Show more

Keywords: Aβ42, Aβ42 supramolecular assemblies, Alzheimer’s disease, biomolecular interactions, extracellular matrix

DOI: 10.3233/JAD-160751

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 991-1005, 2017

Authors: Kim, You Joung | An, Hoyoung | Kim, Binna | Park, Young Shin | Kim, Ki Woong

Article Type: Research Article

Abstract: Over 40% of people with dementia drive, with a two to five times greater accident risk than controls. This has fueled public concerns about the risk of traffic accidents by drivers with dementia (DWD). We compared driving regulations on seniors and DWD between ten European and Asia-Pacific countries to identify key implications for national strategies. Moderate to severe dementia was a reason for driver’s license revocation in all countries. However, regulations on mild dementia varied considerably, with most basing their decisions on severity, rather than simply the presence of dementia. Most used validated assessments, but responsibility for triggering the administrative …process fell on drivers in some countries and on physicians in others. Administrations should consider the following when developing driving policies: 1) ideal regulations on DWD should ensure that restrictions are implemented only when needed; 2) fitness to drive should be assessed using validated instruments; 3) the use of processes that automatically initiate driving competency examinations following a diagnosis of dementia should be explored; and 4) restrictions should be delicately tailored to a range of driving competence levels, and assistive incentives compensating for lost driving privileges should be provided. Show more

Keywords: Automobile driving, competence, dementia, elderly, policy, traffic accidents

DOI: 10.3233/JAD-160762

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1007-1014, 2017

Authors: Lee, Han-Kyu | Kwon, Bumsup | Lemere, Cynthia A. | de la Monte, Suzanne | Itamura, Kyohei | Ha, Austin Y. | Querfurth, Henry W.

Article Type: Research Article

Abstract: Mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor and central controller of cell growth and proliferation, is altered in various models of Alzheimer’s disease (AD). Even less studied or understood in AD is mammalian target of rapamycin complex 2 (mTORC2) that influences cellular metabolism, in part through the regulations of Akt/PKB and SGK. Dysregulation of insulin/PI3K/Akt signaling is another important feature of AD pathogenesis. We found that both total mTORC1 and C2 protein levels and individual C1 and C2 enzymatic activities were decreased in human AD brain samples. In two rodent AD models, mTORC1 and C2 activities were …also decreased. In a neuronal culture model of AD characterized by accumulation of cellular amyloid-β (Aβ)42 , mTORC1 activity was reduced. Autophagic vesicles and markers were correspondingly increased and new protein synthesis was inhibited, consistent with mTORC1 hypofunction. Interestingly, mTORC2 activity in neural culture seemed resistant to the effects of intracellular amyloid. In various cell lines, Aβ expression provoked insulin resistance, characterized by inhibition of stimulated Akt phosphorylation, and an increase in negative mTORC1 regular, p-AMPK, itself a nutrient sensor. Rapamycin decreased phospho-mTOR and to lesser degree p-Rictor. This further suppression of mTORC1 activity protected cells from Aβ-induced toxicity and insulin resistance. More striking, Rictor over-expression fully reversed the Aβ-effects on primary neuronal cultures. Finally, using in vitro assay, Rictor protein addition completely overcame oligomeric Aβ-induced inhibition of the PDK-Akt activation step. We conclude that striking a new balance by restoring mTORC2 abundance and/or inhibition of mTORC1 has therapeutic potential in AD. Show more

Keywords: Akt, Alzheimer’s disease, AMPK, autophagy, insulin resistance, mTOR, mTORC2, Rictor

DOI: 10.3233/JAD-161029

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1015-1036, 2017

Authors: Haddick, Patrick C.G. | Larson, Jessica L. | Rathore, Nisha | Bhangale, Tushar R. | Phung, Qui T. | Srinivasan, Karpagam | Hansen, David V. | Lill, Jennie R. | Alzheimer’s Disease Genetic Consortium (ADGC), Alzheimer’s Disease Neuroimaging Initiative (ADNI) | Pericak-Vance, Margaret A. | Haines, Jonathan | Farrer, Lindsay A. | Kauwe, John S. | Schellenberg, Gerard D. | Cruchaga, Carlos | Goate, Alison M. | Behrens, Timothy W. | Watts, Ryan J. | Graham, Robert R. | Kaminker, Joshua S. | van der Brug, Marcel

Article Type: Research Article

Abstract: The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer’s disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated …with the age of onset of Alzheimer’s disease in APOE ɛ 4 carriers. Across five datasets, p.D358A had a meta P  = 3 ×10-4 and an odds ratio = 1.3, 95% confidence interval 1.12 –1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer’s disease in APOE ɛ 4 carriers. Show more

Keywords: Alzheimer’s disease, astrocytes, IL-6, metalloproteases, microglia

DOI: 10.3233/JAD-160524

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1037-1054, 2017

Authors: Squitti, Rosanna | Mendez, Armando J. | Simonelli, Ilaria | Ricordi, Camillo

Article Type: Research Article

Abstract: Background: Defective copper regulation, primarily referred to as chelatable redox active Cu(II), has been involved in the etiology of diabetes, and Alzheimer’s disease (AD). Objectives: However, no study has determined levels of labile copper non-bound to ceruloplasmin (non-Cp Cu, also known as ‘free’ copper) in the blood of subjects with diabetes compared with that of AD patients. Methods: To this aim, values of non-Cp Cu were measured in 25 Type 1 (T1D) and 31 Type 2 (T2D) subjects and in28 healthy controls, along with measurements of C-reactive protein, glycated hemoglobin A1c , cholesterol, and triglycerides. …Non-Cp Cu levels were compared with those of an AD group previously studied. Results: T2D subjects had significantly higher non-Cp Cu levels than Controls and T1D subjects (both p  < 0.001 after adjusting for age, sex, and body mass index). A multinomial logistic model revealed that a one unit standard deviation increase of non-Cp Cu increased the relative risk of having T2D by 9.64 with respect to Controls (95% CI: 2.86–32.47). The comparison of non-Cp Cu levels in T2D with those of an AD population previously studied shows rising blood non-Cp Cu copper levels from Controls to T2D and AD. Conclusion: These results suggest the involvement of catalytically-active Cu(II) and glucose dysregulation in oxidative stress reactions leading to tissue damage in both diseases. Show more

Keywords: Alzheimer’s disease, copper, diabetes, free copper, Type 1, Type 2

DOI: 10.3233/JAD-161033

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1055-1064, 2017

Authors: Tell-Marti, Gemma | Puig-Butille, Joan Anton | Potrony, Miriam | Plana, Estel | Badenas, Celia | Antonell, Anna | Sanchez-Valle, Raquel | Molinuevo, José L | Lleó, Alberto | Alcolea, Daniel | Fortea, Juan | Fernández-Santiago, Rubén | Clarimón, Jordi | Lladó, Albert | Puig, Susana

Article Type: Research Article

Abstract: Despite the recent identification of some novel risk genes for Alzheimer’s disease (AD), the genetic etiology of late-onset Alzheimer’s disease (LOAD) remains largely unknown. The inclusion of these novel risk genes to the risk attributable to the APOE gene accounts for roughly half of the total genetic variance in LOAD. The evidence indicates that undiscovered genetic factors may contribute to AD susceptibility. In the present study, we sequenced the MC1R gene in 525 Spanish LOAD patients and in 160 controls. We observed that a common MC1R variant p.V92M (rs2228479), not related to pigmentation traits, was present in …72 (14%) patients and 15 (9%) controls and confers increased risk of developing LOAD (OR: 1.99, 95% CI: 1.08–3.64, p  = 0.026), especially in those patients whose genetic risk could not be explained by APOE genotype. This association remains and even increased in the subset of 69 patients with typical AD cerebrospinal fluid profile (OR: 3.40 95% CI: 1.40–8.27, p  = 0.007). We did not find an association between p.V92M and age of onset of AD. Further studies are necessary to elucidate the role of MC1R in brain cells through the different MC1R pathways. Show more

Keywords: Cerebrospinal fluid biomarkers, common variant, late-onset Alzheimer’s disease, melanocortin 1 receptor (MC1R) gene, p.V92M, risk

DOI: 10.3233/JAD-161113

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1065-1074, 2017

Authors: Fitz, Nicholas F. | Carter, Alexis Y. | Tapias, Victor | Castranio, Emilie L. | Kodali, Ravindra | Lefterov, Iliya | Koldamova, Radosveta

Article Type: Research Article

Abstract: ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-free apolipoproteins and regulates the generation of high density lipoproteins. Previously, we have shown that lack of Abca1 significantly increases amyloid deposition and cognitive deficits in Alzheimer’s disease model mice expressing human amyloid-β protein precursor (APP). The goal of this study was to determine if ABCA1 plays a role in memory deficits caused by amyloid-β (Aβ) oligomers and examine neurite architecture of pyramidal hippocampal neurons. Our results confirm previous findings that Abca1 deficiency significantly impairs spatial memory acquisition and retention in the Morris water maze and long-term memory in …novel object recognition of APP transgenic mice at a stage of early amyloid pathology. Neither test demonstrated a significant difference between Abca1 ko and wild-type (WT) mice. We also examined the effect of intra-hippocampal infused Aβ oligomers on cognitive performance of Abca1 ko mice, compared to control infusion of scrambled Aβ peptide. Age-matched WT mice undergoing the same infusions were also used as controls. In this model system, we found a statistically significant difference between WT and Abca1 ko mice infused with scrambled Aβ, suggesting that Abca1 ko mice are vulnerable to the effect of mild stresses. Moreover, examination of neurite architecture in the hippocampi revealed a significant decrease in neurite length, number of neurite segments, and branches in Abca1 ko mice when compared to WT mice. We conclude that mice lacking ABCA1 have basal cognitive deficits that prevent them from coping with additional stressors, which is in part due to impairment of neurite morphology in the hippocampus. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, APP mice, ATP-binding cassette transporter A1 (Abca1), behavior, hippocampal infusion, neurite morphology, radial arm water maze

DOI: 10.3233/JAD-161056

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1075-1085, 2017

Authors: Mohamed, Loqman A. | Zhu, Haihao | Mousa, Youssef M. | Wang, Erming | Qiu, Wei Qiao | Kaddoumi, Amal

Article Type: Research Article

Abstract: Findings from Alzheimer’s disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-β (Aβ) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aβ serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aβ transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by …siRNA knockdown of amylin receptor Ramp3. To explain this finding, amylin effect on Aβ transport proteins expressed at the BBB was evaluated. Findings indicated that cells treated with amylin induced LRP1 expression, a major receptor involved in brain Aβ efflux, in plasma membrane fraction, suggesting intracellular translocation of LRP1 from the cytoplasmic pool. Increased LRP1 in membrane fraction could explain, at least in part, the enhanced uptake and transport of Aβ across the BBB. Collectively, our findings indicated that amylin induced Aβ brain to blood clearance through amylin receptor by inducing LRP1 subcellular translocation to the plasma membrane of the BBB endothelium. Show more

Keywords: Alzheimer’s disease, amylin, amyloid-β, blood-brain barrier, LRP1

DOI: 10.3233/JAD-160800

Citation: Journal of Alzheimer's Disease, vol. 56, no. 3, pp. 1087-1099, 2017