Journal of Alzheimer's Disease - Volume 40, issue 3

Authors: Zhang, Qiang | Descamps, Olivier | Hart, Matthew J. | Poksay, Karen S. | Spilman, Patricia | Kane, Darci J. | Gorostiza, Olivia | John, Varghese | Bredesen, Dale E.

Article Type: Research Article

Abstract: An unbiased screen for compounds that block amyloid-β protein precursor (AβPP) caspase cleavage identified ADDN-1351, which reduced AβPP-C31 by 90%. Target identification studies showed that ADDN-1351 is a TrkA inhibitor, and, in complementary studies, TrkA overexpression increased AβPP-C31 and cell death. TrkA was shown to interact with AβPP and suppress AβPP-mediated transcriptional activation. Moreover, treatment of PDAPP transgenic mice with the known TrkA inhibitor GW441756 increased sAβPPα and the sAβPPα to Aβ ratio. These results suggest TrkA inhibition—rather than NGF activation—as a novel therapeutic approach, and raise the possibility that such an approach may counteract the hyperactive signaling resulting from …the accumulation of active NGF-TrkA complexes due to reduced retrograde transport. The results also suggest that one component of an optimal therapy for Alzheimer's disease may be a TrkA inhibitor. Show more

Keywords: AβPPneo, Alzheimer's disease, amyloid-β protein precursor, GW441756, nerve growth factor, transcriptional activation, TrkA receptor

DOI: 10.3233/JAD-130017

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 605-617, 2014

Authors: Grammas, Paula | Martinez, Joseph | Sanchez, Alma | Yin, Xiangling | Riley, Jarred | Gay, Dylan | Desobry, Katherine | Tripathy, Debjani | Luo, Jinhua | Evola, Marianne | Young, Alice

Article Type: Research Article

Abstract: No disease-modifying therapies are currently available for Alzheimer's disease (AD), a neurodegenerative disorder that affects more than 36 million people worldwide. Although cardiovascular risk factors such as hypertension and diabetes are increasingly implicated as contributing to the development of AD, the mechanisms whereby these factors influence pathological processes in the AD brain have not been defined. Here we propose, for the first time, vascular activation as a relevant mechanism in AD pathogenesis. We explore this hypothesis in two transgenic AD animal models: AD2576APPSwe (AD2576) and LaFerla 3xTg (3xTgAD) mice using the vascular activation inhibitor sunitinib. Our data show that in …both AD animal models, the cerebrovasculature is activated and overexpresses amyloid beta, thrombin, tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and matrix metalloproteinase 9. Oral administration of sunitinib significantly reduces vascular expression of these proteins. Furthermore, sunitinib improves cognitive function, as assessed by several behavioral paradigms, in both AD animal models. Finally, oxidant injury of brain endothelial cells in culture, resulting in expression of inflammatory proteins, is mitigated by sunitinib. The current data, as well as published studies showing cerebrovascular activation in human AD, support further exploration of vascular-based mechanisms in AD pathogenesis. New thinking about AD pathogenesis and novel, effective treatments are urgently needed. Identification of “vascular activation” as a heretofore unexplored target could stimulate translational investigations in this newly defined area, leading to innovative therapeutic approaches for the treatment of this devastating disease. Show more

Keywords: Alzheimer's disease, angiogenesis, behavior, cognitive decline, sunitinib

DOI: 10.3233/JAD-2014-132057

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 619-630, 2014

Authors: Kraijo, Henk | Brouwer, Werner | de Leeuw, Rob | Schrijvers, Guus | van Exel, Job

Article Type: Research Article

Abstract: Background: Health care systems aim to involve as much informal care as possible and dementia patients prefer to stay home as long as they can. In this context, perseverance time (Pt)—the period that the informal carer indicates to be able to maintain current care if the situation remains stable—is an important concept. Objective: The aim of this study was to introduce the concept Pt and validate it in a sample of informal carers of dementia patients living at home. Methods: Data were collected from 223 informal carers of dementia patients. Convergent validity was assessed by looking …at associations of Pt with validated instruments for measuring subjective burden (CSI, CarerQol-7D, and SRB) and happiness (CarerQol-VAS). Content validity was evaluated by performing multivariate correlations between Pt and characteristics of dementia patients, informal carers, and care situations. The Medical Ethics Committee of Utrecht MC advised positively about the study protocol. Results: Correlation coefficients between Pt and the measures of burden CSI, SRB, and CarerQol-VAS were −0.46, −0.63, and 0.23 (p < 0.01), respectively. Health of dementia patient, informal carer living apart from the patient, and male gender of caregiver were positively associated with Pt; need for supervision, intensity of informal care provision, and reductions in working hours and hobbies in order to be able to provide care were negatively associated. Conclusions: Pt is helpful in monitoring need for support and planning the transition of care from home to nursing home. This study provides a first indication of its validity, but replication is necessary. Show more

Keywords: Burden, dementia, informal care, perseverance time, validity

DOI: 10.3233/JAD-132420

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 631-642, 2014

Authors: Ramos-Fernández, Eva | Tajes, Marta | Palomer, Ernest | ILL-Raga, Gerard | Bosch-Morató, Mònica | Guivernau, Biuse | Román-Dégano, Irene | Eraso-Pichot, Abel | Alcolea, Daniel | Fortea, Juan | Nuñez, Laura | Paez, Antonio | Alameda, Francesc | Fernández-Busquets, Xavier | Lleó, Alberto | Elosúa, Roberto | Boada, Mercé | Valverde, Miguel A. | Muñoz, Francisco J.

Article Type: Research Article

Abstract: Glycation and nitrotyrosination are pathological posttranslational modifications that make proteins prone to losing their physiological properties. Since both modifications are increased in Alzheimer's disease (AD) due to amyloid-β peptide (Aβ) accumulation, we have studied their effect on albumin, the most abundant protein in cerebrospinal fluid and blood. Brain and plasmatic levels of glycated and nitrated albumin were significantly higher in AD patients than in controls. In vitro turbidometry and electron microscopy analyses demonstrated that glycation and nitrotyrosination promote changes in albumin structure and biochemical properties. Glycated albumin was more resistant to proteolysis and less uptake by hepatoma cells occurred. Glycated …albumin also reduced the osmolarity expected for a solution containing native albumin. Both glycation and nitrotyrosination turned albumin cytotoxic in a cell type-dependent manner for cerebral and vascular cells. Finally, of particular relevance to AD, these modified albumins were significantly less effective in avoiding Aβ aggregation than native albumin. In summary, nitrotyrosination and especially glycation alter albumin structural and biochemical properties, and these modifications might contribute for the progression of AD. Show more

Keywords: Albumin, Alzheimer's disease, amyloid, glycation, nitrotyrosination, oxidative stress

DOI: 10.3233/JAD-130914

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 643-657, 2014

Authors: Yang, Hongqian | Lyutvinskiy, Yaroslav | Herukka, Sanna-Kaisa | Soininen, Hilkka | Rutishauser, Dorothea | Zubarev, Roman A.

Article Type: Research Article

Abstract: Background: Patients with mild cognitive impairment (MCI) have varying risks of progression to Alzheimer’s disease (AD). Objective: To test the utility of the relative abundances of blood plasma polypeptides for predicting the risk of AD progression. Methods: 119 blood plasma samples of patients with MCI with different outcomes (stable MCI and progressive MCI) were analyzed by untargeted, label-free shotgun proteomics. Predictive biomarkers of progressive MCI were selected by multivariate analysis, followed by cross-validation of the predictive model. Results: The best model demonstrated the accuracy of ca. 79% in predicting progressive MCI. Sex differences of …the predictive biomarkers were also assessed. We have identified some sex-specific protein biomarkers, e.g., alpha-2-macrogloblin (A2M), which strongly correlates with female AD progression but not with males. Conclusion: Significant sex bias in AD-specific biomarkers underscores the necessity of selecting sex-balanced cohort in AD biomarker studies, or using sex-specific models. Blood protein biomarkers are found to be promising for predicting AD progression in clinical settings. Show more

Keywords: Biomarkers, human blood plasma, label-free quantification, mass spectrometry

DOI: 10.3233/JAD-132102

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 659-666, 2014

Authors: Hanzel, Cecilia E. | Iulita, M. Florencia | Eyjolfsdottir, Helga | Hjorth, Erik | Schultzberg, Marianne | Eriksdotter, Maria | Cuello, A. Claudio

Article Type: Research Article

Abstract: The expression of matrix metallo-proteases (MMP-2, MMP-3, MMP-7, and MMP-9), plasminogen and their regulators (TIMP-1, tissue plasminogen activator and neuroserpin) was investigated in cerebrospinal fluid (CSF) from subjective cognitive impairment (SCI) subjects, mild cognitive impairment (MCI), and Alzheimer's disease (AD) cases. ELISA analysis revealed a significant increase in MMP-3 protein levels in CSF from AD subjects, compared to age-matched SCI and MCI cases. No significant differences in MMP-2 and MMP-9 protein levels were detected between the three groups. MMP-7 was undetectable in all three groups. MCI individuals exhibited increased levels of the metallo-protease inhibitor TIMP-1 in CSF as well as …higher plasminogen and neuroserpin expression, compared to SCI subjects. Levels of tissue plasminogen activator (tPA) were significantly reduced in AD CSF. Correlation analysis revealed a significant positive association between MMP-3, p-tau, and total-tau levels. Conversely, there was a significant negative correlation between this protease and Mini-Mental State Examination (MMSE) scores. tPA positively correlated with amyloid-β levels in CSF and with MMSE scores. Our results suggest that MMP-3 and tPA, in combination with current amyloid-β and tau biomarkers, may have potential as surrogate indicators of an ongoing AD pathology. Show more

Keywords: Alzheimer's disease, biomarkers, metallo-proteases, neuroserpin, plasminogen

DOI: 10.3233/JAD-132282

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 667-678, 2014

Authors: Piaceri, Irene | Pradella, Silvia | Cupidi, Chiara | Nannucci, Serena | Polito, Cristina | Bagnoli, Silvia | Tedde, Andrea | Smirne, Nicoletta | Anfossi, Maria | Gallo, Maura | Bernardi, Livia | Colao, Rosanna | Maletta, Raffaele | Bruni, Amalia Cecilia | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Research Article

Abstract: Background: Progranulin protein (PGRN) is a cysteine-rich growth factor encoded by the progranulin gene (GRN). PGRN mutations were identified in patients with frontotemporal lobar degeneration (FTLD) and recently its role as risk factor has been described in patients with probable Alzheimer’s disease (AD). To date, more than 100 genetic variants in GRN gene have been described and the pathogenic nature is still unclear for almost 36% of them. Objective: Here, we describe three clinical cases carrying the PGRN variation Cys139Arg in order to increase the knowledge on the association of this variant to the clinical spectrum of FTLD. …Methods: The genetic analysis was performed using high resolution melting analysis. The Human Progranulin ELISA Kit was used in order to determine PGRN expression levels in the plasma samples. Results: The three patients carrying the genetic variation showed three final different clinical diagnosis, respectively behavioral frontotemporal dementia, semantic dementia, and corticobasal syndrome, thus underlining the clinical heterogeneity typically associated with GRN mutations. All cases shared similar plasma PGRN levels that resulted intermediate between those measured in controls and in GRN null mutation carriers, showing a partial reduction of the protein in plasma. Moreover, according to the bioinformatics software, the Cys139Arg variation causes a decreased stability of the structure of the protein. Conclusion: We describe three new patients affected by neurological syndromes included in the clinical spectrum of FTLD carrying the Cys139Arg genetic variant, thus suggesting a possible implication in the pathogenesis of FTLD. Show more

Keywords: Cys139Arg, frontotemporal dementia, mutation, plasma, progranulin

DOI: 10.3233/JAD-132126

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 679-685, 2014

Authors: Kilimann, Ingo | Grothe, Michel | Heinsen, Helmut | Alho, Eduardo Joaquim Lopez | Grinberg, Lea | Amaro Jr., Edson | dos Santos, Gláucia Aparecida Bento | da Silva, Rafael Emídio | Mitchell, Alex J. | Frisoni, Giovanni B. | Bokde, Arun L.W. | Fellgiebel, Andreas | Filippi, Massimo | Hampel, Harald | Klöppel, Stefan | Teipel, Stefan J.

Article Type: Research Article

Abstract: Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which …were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD. Show more

Keywords: Atrophy, biomarker, cholinergic system, dementia, European DTI Study on Dementia

DOI: 10.3233/JAD-132345

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 687-700, 2014

Authors: Bedse, Gaurav | Romano, Adele | Cianci, Silvia | Lavecchia, Angelo M. | Lorenzo, Pace | Elphick, Maurice R. | LaFerla, Frank M. | Vendemiale, Gianluigi | Grillo, Caterina | Altieri, Fabio | Cassano, Tommaso | Gaetani, Silvana

Article Type: Research Article

Abstract: The endocannabinoid system has gained much attention as a new potential pharmacotherapeutic target in various neurodegenerative diseases, including Alzheimer's disease (AD). However, the association between CB1 alterations and the development of AD neuropathology is unclear and often contradictory. In this study, brain CB1 mRNA and CB1 protein levels were analyzed in 3 × Tg-AD mice and compared to wild-type littermates at 2, 6 and 12 months of age, using in-situ hybridization and immunohistochemistry, respectively. Semiquantitative analysis of CB1 expression focused on the prefrontal cortex (PFC), prelimbic cortex, dorsal hippocampus (DH), basolateral amygdala complex (BLA), and ventral hippocampus (VH), all areas …with high CB1 densities that are strongly affected by neuropathology in 3 × Tg-AD mice. At 2 months of age, there was no change in CB1 mRNA and protein levels in 3 × Tg-AD mice compared to Non-Tg mice in all brain areas analyzed. However, at 6 and 12 months of age, CB1 mRNA levels were significantly higher in PFC, DH, and BLA, and lower in VH in 3 × Tg-AD mice compared to wild-type littermates. CB1 immunohistochemistry revealed that CB1 protein expression was unchanged in 3 × Tg-AD at 2 and 6 months of age, while a significant decrease in CB1 receptor immunoreactivity was detected in the BLA and DH of 12-month-old 3 × Tg-AD mice, with no sign of alteration in other brain areas. The altered CB1 levels appear, rather, to be age-and/or pathology-dependent, indicating an involvement of the endocannabinoid system in AD pathology and supporting the ECS as a potential novel therapeutic target for treatment of AD. Show more

Keywords: 3 × Tg-AD mice, Alzheimer's disease, basolateral amygdala complex, CB1 mRNA, CB1 receptor, endocannabinoid system, hippocampus, prefrontal cortex

DOI: 10.3233/JAD-131910

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 701-712, 2014

Authors: Suszyńska-Zajczyk, Joanna | Łuczak, Magdalena | Marczak, Łukasz | Jakubowski, Hieronim

Article Type: Research Article

Abstract: Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Bleomycin hydrolase (BLMH) participates in Hcy metabolism and is also linked to AD. The inactivation of the Blmh gene in mice causes accumulation of Hcy-thiolactone in the brain and increases susceptibility to Hcy-thiolactone-induced seizures. To gain insight into brain-related Blmh function, we used two-dimensional IEF/SDS-PAGE gel electrophoresis and MALDI-TOF/TOF mass spectrometry to examine brain proteomes of Blmh−/− mice and their Blmh+/+ littermates fed with a hyperhomocysteinemic high-Met or a control diet. We found that: 1) proteins involved in brain-specific function (Ncald, Nrgn, Stmn1, Stmn2), antioxidant defenses (Aop1), cell …cycle (RhoGDI1, Ran), and cytoskeleton assembly (Tbcb, CapZa2) were differentially expressed in brains of Blmh-null mice; 2) hyperhomocysteinemia amplified effects of the Blmh−/− genotype on brain protein expression; 3) proteins involved in brain-specific function (Pebp1), antioxidant defenses (Sod1, Prdx2, DJ-1), energy metabolism (Atp5d, Ak1, Pgam-B), and iron metabolism (Fth) showed differential expression in Blmh-null brains only in hyperhomocysteinemic animals; 4) most proteins regulated by the Blmh−/− genotype were also regulated by high-Met diet, albeit in the opposite direction; and 5) the differentially expressed proteins play important roles in neural development, learning, plasticity, and aging and are linked to neurodegenerative diseases, including AD. Taken together, our findings suggest that Blmh interacts with diverse cellular processes from energy metabolism and anti-oxidative defenses to cell cycle, cytoskeleton dynamics, and synaptic plasticity essential for normal brain homeostasis and that modulation of these interactions by hyperhomocysteinemia underlies the involvement of Hcy in AD. Show more

Keywords: Alzheimer's disease, bleomycin hydrolase, Blmh-null mouse, brain proteome, dietary hyperhomocysteinemia, homocysteine, neurodegenerative diseases

DOI: 10.3233/JAD-132033

Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 713-726, 2014