Journal of Alzheimer's Disease - Volume 35, issue 2

Authors: Lira-De León, Karla I. | García-Gutiérrez, Ponciano | Serratos, Iris N. | Palomera-Cárdenas, Marianela | Figueroa-Corona, María del P. | Campos-Peña, Victoria | Meraz-Ríos, Marco A.

Article Type: Research Article

Abstract: Abnormal tau filaments are a hallmark of Alzheimer's disease. Anionic dyes such as Congo Red, Thiazine Red, and Thioflavin S are able to induce tau fibrillization in vitro. SH-SY5Y cells were incubated with each dye for seven days leading to intracellular aggregates of tau protein, with different morphological characteristics. Interestingly, these tau aggregates were not observed when the Methylene Blue dye was added to the cell culture. In order to investigate the molecular mechanisms underlying this phenomenon, we developed a computational model for the interaction of the tau paired helical filament (PHF) core with every dye by docking analysis. The …polar/electrostatic and nonpolar contribution to the free binding energy in the tau PHF core-anionic dye interaction was determined. We found that the tau PHF core can generate a positive net charge within the binding site localized at residuesLys311 and Lys340 (numbering according to the longest isoform hTau40). These residues are important for the binding affinity of the negative charges present in the anionic dyes causing an electrostatic environment that stabilizes the complex. Tau PHF core protofibril-Congo Red interaction has a stronger binding affinity compared to Thiazine Red or Thioflavin S. By contrast, the cationic dye Methylene Blue does not bind to nor stabilize the tau PHF core protofibrils. These results characterize the driving forces responsible for the binding of tau to anionic dyes leading to their self-aggregation and suggest that Methylene Blue may act as a destabilizing agent of tau aggregates. Show more

Keywords: Alzheimer's disease, Congo Red, docking, Methylene Blue, SH-SY5Y cells, tau aggregation, tauopathies, Thiazine Red, Thiofavin S

DOI: 10.3233/JAD-121765

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 319-334, 2013

Authors: Hébert, Sébastien S. | Wang, Wang-Xia | Zhu, Qi | Nelson, Peter T.

Article Type: Research Article

Abstract: MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual diseases such as Alzheimer's disease (AD), making disease-to-disease comparisons impossible. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent …ND subtypes. All cases had short postmortem intervals, relatively high-quality RNA, and state-of-the-art neuropathological diagnoses. The resulting data (over 113 million reads in total, averaging 5.6 million reads per sample) and secondary expression analyses constitute an unprecedented look into the human cerebral cortical miRNome at a nucleotide resolution. While we find no apparent changes in isomiR or miRNA editing patterns in correlation with ND pathology, our results validate and extend previous miRNA profiling studies with regard to quantitative changes in NDs. In agreement with this idea, we provide independent cohort validation for changes in miR-132 expression levels in AD (n = 8) and FTLD (n = 14) cases when compared to controls (n = 8). The identification of common and ND-specific putative novel brain miRNAs and/or short-hairpin molecules is also presented. The challenge now is to better understand the impact of these and other alterations on neuronal gene expression networks and neuropathologies. Show more

Keywords: Alzheimer's disease, deep sequencing, dementia with Lewy bodies, frontotemporal lobar dementia, hippocampal sclerosis, isomiR, microRNA, progressive supranuclear palsy

DOI: 10.3233/JAD-122350

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 335-348, 2013

Authors: Di Santo, Simona Gabriella | Prinelli, Federica | Adorni, Fulvio | Caltagirone, Carlo | Musicco, Massimo

Article Type: Research Article

Abstract: Background: Randomized clinical trials have evaluated the efficacy of acetylcholinesterase inhibitors (AChE-Is) and memantine across a wide range of Alzheimer’s disease (AD) severity. However, these drugs are prescribed and reimbursed according to precise upper and lower cut off scores of cognitive tests. Objectives: To verify whether the efficacy of pharmacological treatment had any dependence on the severity of dementia in AD patients. Methods: Published English-language randomized, placebo-controlled trials evaluating the efficacy of AChE-Is or memantine at any dose, over any length of time, in patients with any severity of dementia due to AD were included. Cognitive, …behavioral, and functional outcomes were extracted from each study and multiple outcomes from the same trial were pooled to obtain a unique indicator of efficacy for cognition, functional impairment, and behavioral and psychological disturbances. The existence of a relationship between size of the treatment effect and severity of dementia, measured with the Mini-Mental State Examination, was determined using parametric and non-parametric correlation analyses. Results: Both AChE-Is and memantine had significant effects on cognition. Functional and psycho-behavioral outcomes were reported less frequently but also showed significant efficacy of treatment. High heterogeneity among studies was found within and between the different drugs. The efficacy of all drugs except memantine was independent from dementia severity in all domains. Memantine effect on functional impairment was better in more severe patients. Conclusions: The modest beneficial effects of anti-dementia drugs on cognition are independent from dementia severity. Memantine is more effective on functional incompetence only in severe patients. Show more

Keywords: Activities of daily living, Alzheimer's disease, behavioral and psychological symptoms of dementia, cholinesterase inhibitors, cognition disorders, memantine, meta-analysis

DOI: 10.3233/JAD-122140

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 349-361, 2013

Authors: Hall, James R. | Wiechmann, April R. | Johnson, Leigh A. | Edwards, Melissa | Barber, Robert C. | Winter, A. Scott | Singh, Meharvan | O'Bryant, Sid E. | for the Texas Alzheimer's Research and Care Consortium

Article Type: Research Article

Abstract: Numerous serum and plasma based biomarkers of systemic inflammation have been linked to both neuropsychiatric disorders and Alzheimer's disease (AD). The present study investigated the relationship of clinical biomarkers of cardiovascular risk (cholesterol, triglycerides, and homocysteine) and a panel of markers of systemic inflammation (CRP, TNF-α, IL1-ra, IL-7, IL-10, IL-15, IL-18) and microvascular pathology (ICAM-1, VCAM-1) to neuropsychiatric symptoms in a sample with mild AD. Biomarker data was analyzed on a sample of 194 diagnosed with mild to moderate probable AD. The sample was composed of 127 females and 67 males. The presence of neuropsychiatric symptoms was gathered from interview …with caretakers/family members using the Neuropsychiatric Inventory. For the total sample, IL-15, VCAM (vascular adhesion molecule), and triglycerides were significantly and negatively related to number of neuropsychiatric symptoms, and total cholesterol and homocysteine were positively related and as a group accounted for 16.1% of the variance. When stratified by gender, different patterns of significant biomarkers were found with relationships more robust for males for both total symptoms and symptom clusters. A combination of biomarkers of systemic inflammation, microvascular pathology, and clinical biomarkers of cardiovascular risk can account for a significant portion of the variance in the occurrence of neuropsychiatric symptoms in AD supporting a vascular and inflammatory component of psychiatric disorders found in AD. Gender differences suggest distinct impact of specific risks with total cholesterol, a measure of cardiovascular risk, being the strongest marker for males and IL-15, a marker of inflammation, being the strongest for females. Show more

Keywords: Alzheimer's disease, biomarkers, gender, neuropsychiatric symptoms

DOI: 10.3233/JAD-122359

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 363-371, 2013

Authors: Han, Guangchun | Wang, Jiajia | Zeng, Fan | Feng, Xuemei | Yu, Jun | Cao, Hong-Yuan | Yi, Xu | Zhou, Huadong | Jin, Lee-Way | Duan, Yong | Wang, Yan-Jiang | Lei, Hongxing

Article Type: Research Article

Abstract: Blood transcriptome has emerged as a potential resource for the discovery of biomarkers for Alzheimer's disease (AD). However, the validity of blood transcriptome in the early diagnosis of AD has yet to be extensively tested. In this work, we analyzed published data on AD blood transcriptome and revealed the characteristic perturbation of cellular functional units, including upregulation of environmental responses (immune response, survival/death signaling, and cellular recycling) and down-regulation of core metabolism (energy metabolism and translation/splicing). This characteristic perturbation was unique to AD based on the comparison with blood transcriptome from other neurological disorders and complex diseases. More importantly, similar …perturbation was observed in both AD and mild cognitive impairment (MCI) groups. This perturbation pattern was further validated in our independent microarray experiment in a small Chinese cohort. In addition, the potential effect of aging and lifestyle on blood transcriptome was discussed. Based on the analyses, we propose that the transformation of the blood transcriptome in AD is an integrated part of the disease mechanism and has potential to serve as a reliable biomarker for assisting the early diagnosis as well as monitoring purpose. Therefore, more independent studies on blood transcriptome of AD and MCI with larger sample size are warranted. Show more

Keywords: Blood, energy metabolism, immune response, microarray, ribosome

DOI: 10.3233/JAD-121963

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 373-386, 2013

Authors: Wen, Yanan | Miyashita, Akinori | Kitamura, Nobutaka | Tsukie, Tamao | Saito, Yuko | Hatsuta, Hiroyuki | Murayama, Shigeo | Kakita, Akiyoshi | Takahashi, Hitoshi | Akatsu, Hiroyasu | Yamamoto, Takayuki | Kosaka, Kenji | Yamaguchi, Haruyasu | Akazawa, Kohei | Ihara, Yasuo | Kuwano, Ryozo | Japanese Alzheimer's Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [ = 0.05/19]), which was supported by means …of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE ε4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD. Show more

Keywords: Alzheimer's disease, association, neuropathology, single-nucleotide polymorphism, SORL1

DOI: 10.3233/JAD-122395

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 387-394, 2013

Authors: Lee, Sangmook | Zemianek, Jill | Shea, Thomas B.

Article Type: Research Article

Abstract: Alzheimer's disease is accompanied by the accumulation of amyloid-β (Aβ) and the microtubule-associated protein tau. Aβ toxicity is dependent upon its form as well as concentration. Soluble Aβ oligomers, rather than the fibrillar forms that comprise senile plaques, represent the toxic form and are correlated with the extent of dementia. Since soluble Aβ perturbs synaptic function, we examined the impact of exogenously applied Aβ on signaling in neurons cultured on multi-electrode arrays. We observed that subcytotoxic levels (10 nm–5 μM) of human Aβ1-42 perturbed synaptic transmission within hours. This perturbation suggests that mild cognitive problems, perhaps undetected by traditional …clinical approaches, can accompany critical accumulation of Aβ. This effect was prevented by the calcium chelator BAPTA, indicating a requirement for calcium for inhibition of signaling by Aβ. Aβ-induced inhibition of signaling was not prevented by application of MK-801 or nimodipine (antagonists of the NMDA receptor and L-type voltage-sensitive calcium channel, respectively) suggesting that Aβ may induce influx by either channel, or additional channels, or that neurons contained sufficient calcium to mediate the impact of Aβ. Signaling returned to original levels within 120 h after administration of a single dosage of Aβ, or within 24 h after replacement of medium with fresh medium lacking Aβ, suggesting that intervention to reduce Aβ levels at their first appearance may prevent permanent neurotoxicity. Show more

Keywords: Amyloid-β, calcium, cortical neurons, culture, synaptic signaling

DOI: 10.3233/JAD-122452

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 395-402, 2013

Authors: Martinez-Mir, Amalia | González-Pérez, Antonio | Gayán, Javier | Antúnez, Carmen | Marín, Juan | Boada, Mercé | Lopez-Arrieta, Jesús María | Alzheimer's Disease Neuroimaging Initiative | Fernández, Evaristo | Ramírez-Lorca, Reposo | Sáez, María Eugenia | Ruiz, Agustín | Scholl, Francisco G. | Real, Luis Miguel

Article Type: Research Article

Abstract: The interaction between neurexins and neuroligins promotes the formation of functional synaptic structures. Recently, it has been reported that neurexins and neuroligins are proteolytically processed by presenilins at synapses. Based on this interaction and the role of presenilins in familial Alzheimer's disease (AD), we hypothesized that dysfunction of the neuroligin-neurexin pathway might be associated with AD. To explore this hypothesis, we carried out a meta-analysis of five genome-wide association studies (GWAS) comprising 1, 256 SNPs in the NRXN1, NRXN2, NRXN3, and NLGN1 genes (3,009 cases and 3,006 control individuals). We identified a marker in the NRXN3 gene (rs17757879) that showed …a consistent protective effect in all GWAS, however, the statistical significance obtained did not resist multiple testing corrections (OR = 0.851, p = 0.002). Nonetheless, gender analysis revealed that this effect was restricted to males. A combined meta-analysis of the former five GWAS together with a replication Spanish sample consisting of 1,785 cases and 1,634 controls confirmed this observation (rs17757879, OR = 0.742, 95% CI = 0.632–0.872, p = 0.00028, final meta-analysis). We conclude that NRXN3 might have a role in susceptibility to AD in males. Show more

Keywords: Alzheimer's disease, genetics, genome-wide association study, meta-analysis, neurexins, neuroligins, NRXN3

DOI: 10.3233/JAD-122257

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 403-412, 2013

Authors: Vercambre, Marie-Noël | Berr, Claudine | Ritchie, Karen | Kang, Jae H.

Article Type: Research Article

Abstract: Background: Persons with vascular disorders are at higher risk of cognitive decline. Objective: To determine whether caffeine may be associated with cognitive decline reduction in elderly at high vascular risk. Methods: We included 2,475 women aged 65+ years in the Women’s Antioxidant Cardiovascular Study, a randomized trial of antioxidants and B vitamins for cardiovascular disease secondary prevention. We ascertained regular caffeine intake at baseline (1995–1996) using a validated 116 item-food frequency questionnaire. From 1998–2000 to 2005–2006, we administered four telephone cognitive assessments at two-year intervals evaluating global cognition, verbal memory, and category fluency. The primary outcome …was the change in global cognitive score, which was the average of the z-scores of all tests. We used generalized linear models for repeated measures that were adjusted for various sociodemographic, health, and lifestyle factors to evaluate the difference in cognitive decline rates across quintiles of caffeine intake. Results: We observed significantly slower rates of cognitive decline with increasing caffeine intake (p-trend = 0.02). The rate difference between the highest and lowest quintiles of usual caffeine intake (>371 versus <30 mg/day) was equivalent to that observed between those who were 7 years apart in age (p = 0.006). Consumption of caffeinated coffee was significantly related to slower cognitive decline (p-trend = 0.05), but not other caffeinated products (e.g., decaf, tea, cola, chocolate). We conducted interaction analyses and observed stronger associations in women assigned to vitamin B supplementation (p-interaction = 0.02). Conclusions: Caffeine intake was related to moderately better cognitive maintenance over 5 years in older women with vascular disorders. Show more

Keywords: Aging, caffeine, cognition, cohort studies, epidemiology, risk factors

DOI: 10.3233/JAD-122371

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 413-421, 2013

Article Type: Other

DOI: 10.3233/JAD-122372

Citation: Journal of Alzheimer's Disease, vol. 35, no. 2, pp. 423-425, 2013