Journal of Alzheimer's Disease - Volume 48, issue 3

Authors: Hu, Shunze | Wang, Huan | Chen, Kun | Cheng, Peng | Gao, Shutao | Liu, Jian | Li, Xiao | Sun, Xuying

Article Type: Research Article

Abstract: MicroRNAs (miRNAs) are small (∼22-nucleotide [nt]) noncoding RNAs that regulate biological processes at the post-transcriptional level. Dysregulation of specific miRNAs leads to impaired synaptic plasticity resulting in Alzheimer’s disease (AD). Amyloid-β (Aβ) accumulation is the most important pathogenic factor for AD development. Therefore, focusing on Aβ-targeted miRNAs may have therapeutic implications for AD. We found that miR-34c, a miRNA that was previously reported to be upregulated in a transgenic AD model and patients, was significantly increased in hippocampal neurons exposed to Aβ. Western blots and luciferase assay confirmed that increased miR-34c was closely related to VAMP2 reduction. Furthermore, miR-34c blockade …upregulated VAMP2 expression and rescued synaptic failure as well as learning and memory deficits caused by Aβ. The Aβ-miR-34c-VAMP2 pathway mediates the sustained VAMP2 reduction in AD patients and provides a novel underlying epigenetic mechanism for attenuation of Aβ toxicity in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, miR-34c, VAMP2

DOI: 10.3233/JAD-150432

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 673-686, 2015

Authors: Meier, Shelby | Bell, Michelle | Lyons, Danielle N. | Ingram, Alexandria | Chen, Jing | Gensel, John C. | Zhu, Haining | Nelson, Peter T. | Abisambra, Jose F.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is pathologically characterized by the formation of extracellular amyloid plaques and intraneuronal tau tangles. We recently identified that tau associates with proteins known to participate in endoplasmic reticulum (ER)-associated degradation (ERAD); consequently, ERAD becomes dysfunctional and causes neurotoxicity. We hypothesized that tau associates with other ER proteins, and that this association could also lead to cellular dysfunction in AD. Portions of human AD and non-demented age matched control brains were fractionated to obtain microsomes, from which tau was co-immunoprecipitated. Samples from both conditions containing tau and its associated proteins were analyzed …by mass spectrometry. In total, we identified 91 ER proteins that co-immunoprecipitated with tau; 15.4% were common between AD and control brains, and 42.9% only in the AD samples. The remainder, 41.8% of the proteins, was only seen in the control brain samples. We identified a variety of previously unreported interactions between tau and ER proteins. These proteins participate in over sixteen functional categories, the most abundant being involved in RNA translation. We then determined that association of tau with these ER proteins was different between the AD and control samples. We found that tau associated equally with the ribosomal protein L28 but more robustly with the ribosomal protein P0. These data suggest that the differential association between tau and ER proteins in disease could reveal the pathogenic processes by which tau induces cellular dysfunction. Show more

Keywords: Alzheimer’s disease, co-immunoprecipitation, endoplasmic reticulum, mass spectrometry, microsome, ribosome, tau, tauopathies

DOI: 10.3233/JAD-150298

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 687-702, 2015

Authors: Guido, Davide | Morandi, Gabriella | Palluzzi, Fernando | Borroni, Barbara

Article Type: Research Article

Abstract: In this paper, we reconstructed the medical history of frontotemporal dementia (FTD) by reviewing the literature and analyzing papers with the highest impact through citation index. Several research studies and groups involved in FTD have been reviewed. An increasing amount of knowledge has been made available in the last 20 years through a large number of publications, leading to a better definition of the genetic and clinical bases of the disease. A total of 1,436 references (articles and reviews), published in 395 journals, were retrieved through the Scopus database. The two highest publication peaks (i.e., largest number of publications) were …found in 2000 and 2008. The most cited papers considering both total citation number and the number of citations within the first two years after publication refer to: (i) the genetic bases of FTD, (ii) the clinical criteria that progressively refined the different FTD phenotypes, and (iii) FTD epidemiology. Advanced neuroimaging techniques, genotype-phenotype heterogeneity, and animal models gave us a broader understanding of various aspects of the disorder. These findings confirm the great interest in FTD research. The analysis of the literature might help in guiding future goals in the field. Show more

Keywords: Bibliometric analysis, citations analysis, frontotemporal dementia, frontotemporal lobar degeneration

DOI: 10.3233/JAD-150275

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 703-709, 2015

Authors: Duits, Flora H. | Hernandez-Guillamon, Mar | Montaner, Joan | Goos, Jereon D.C. | Montañola, Alex | Wattjes, Mike P. | Barkhof, Frederik | Scheltens, Philip | Teunissen, Charlotte E. | van der Flier, Wiesje M.

Article Type: Research Article

Abstract: Matrix metalloproteinases (MMPs) are a family of enzymes able to degrade components of the extracellular matrix, which is important for normal blood-brain barrier function. Their function is regulated by tissue inhibitors of matrix metalloproteinases (TIMPs). We investigated whether MMPs and TIMPs in cerebrospinal fluid (CSF) and plasma were altered in Alzheimer’s disease (AD) and vascular dementia (VaD), and whether this effect was modified by presence of cerebral micro-bleeds in AD patients. In addition, we assessed associations of MMPs and TIMPs with CSF amyloid-β1 - 42 (Aβ42 ), tau, and tau phosphorylated at threonine-181 (p-tau). We measured MMP2, MMP9, and MMP10, and …TIMP1 and TIMP2 in CSF and plasma of 52 AD patients, 26 matched controls, and 24 VaD patients. AD patients showed higher plasma MMP2 levels compared to VaD patients (p  <  0.05), and higher CSF MMP10 levels compared to controls (p  <  0.05). Microbleeds in AD were associated with lower CSF TIMP1, TIMP2 and MMP9 in a dose-response relation. In addition, CSF MMP2 was associated with p-tau (St.B 0.23, p  <  0.05), and CSF MMP10 with tau (St.B 0.38, p  <  0.001) and p-tau (St.B 0.40, p  <  0.001). Our findings suggest involvement of MMP2 and MMP10 in AD pathology. Lower levels of TIMPs in AD patients with microbleeds suggest less MMP inhibition in patients with concurrent cerebral microbleeds, which may hypothetically lead to a more vulnerable blood-brain barrier in these patients. Show more

Keywords: Alzheimer’s disease, cerebral amyloid angiopathy, cerebrospinal fluid, matrix metalloproteinases, microbleeds, tissue inhibitors of matrix metalloproteinases

DOI: 10.3233/JAD-143186

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 711-720, 2015

Authors: Soto-Gordoa, Myriam | Arrospide, Arantzazu | Moreno-Izco, Fermín | Martínez-Lage, Pablo | Castilla, Iván | Mar, Javier

Article Type: Research Article

Abstract: Risk and protective factors such as obesity, hypercholesterolemia, physical activity, and hypertension can play a role in the development of dementia. Our objective was to measure the effect of modification of risk and protective factors on the prevalence and economic burden of dementia in the aging Spanish population during 2010–2050. A discrete event simulation model including risk and protective factors according to CAIDE (Cardiovascular Risk Factors, Aging and Incidence of Dementia) Risk Score was built to represent the natural history of dementia. Prevalence of dementia was calculated from 2010 to 2050 according to different scenarios of risk factor prevalence to …assess the annual social and health care costs of dementia. The model also supplied hazard ratios for dementia. Aging will increase between 49% and 16% each decade in the number of subjects with dementia. The number of working-age individuals per person with dementia will decrease to a quarter by 2050. An intervention leading to a 20% change in risk and protective factors would reduce dementia by 9% , prevent over 100,000 cases, and save nearly 4,900 million euros in 2050. Switching individuals from a group with a specific risk factor to one without it nearly halved the risk of the development of dementia. Dementia prevalence will grow unmanageable if effective prevention strategies are not developed. Interventions aiming to reduce modifiable risk factor prevalence represent valid and effective alternatives to reduce dementia burden. However, further research is needed to identify causal relationships between dementia and risk factors. Show more

Keywords: Alzheimer’s disease, dementia, hypercholesterolemia, hypertension, obesity, primary prevention, projections, physical activity, risk factors

DOI: 10.3233/JAD-150233

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 721-730, 2015

Authors: Hong, Hyun-Seok | Maezawa, Izumi | Petrlova, Jitka | Zhao, Xiao-Yan | C. Voss, John | Jin, Lee-Way

Article Type: Research Article

Abstract: Amyloid-β (Aβ) protein causes neurotoxicity and its abnormal aggregation into amyloid is a pathological hallmark of Alzheimer’s disease (AD). Cellular proteins able to interact with Aβ or its precursor, AβPP (amyloid-β protein precursor), may regulate Aβ production and neurotoxicity. We identified a brain-enriched type I transmembrane protein, tomoregulin (TR), that directly binds Aβ and Aβ oligomers (AβO). TR co-immunoprecipitated with Aβ and AβO in cultured cells and co-localized with amyloid plaques and intraneuronal Aβ in the 5xFAD AD mouse model. TR was also enriched in astrocytic processes reactive to amyloid plaques. Surface plasmon resonance spectroscopy studies showed that the extracellular …domain of TR binds to AβO with a high affinity (KD  = 76.8 nM). Electron paramagnetic resonance spectroscopy also demonstrated a physical interaction between spin-labeled Aβ and the TR extracellular domain in solution. Furthermore, TR also interacted with AβPP and enhanced its cleavage by α -secretase. Both cellular expression of TR and application of recombinant TR extracellular domain protected N2a neurons from AβO-induced neuronal death. These data provide first evidence that neuronal and astrocytic expression of TR is intimately related to Aβ metabolism and toxicity, and could be neuroprotective through its direct interaction with Aβ and AβPP. Show more

Keywords: Alzheimer’s disease, amyloid, binding, neuroprotection, neurotoxicity, tomoregulin

DOI: 10.3233/JAD-150318

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 731-743, 2015

Authors: Foraker, Jessica | Millard, Steven P. | Leong, Lesley | Thomson, Zachary | Chen, Sunny | Keene, C. Dirk | Bekris, Lynn M. | Yu, Chang-En

Article Type: Research Article

Abstract: The ɛ 4 allele of the human apolipoprotein E gene (APOE ) is a well-proven genetic risk factor for the late onset form of Alzheimer’s disease (AD). However, the biological mechanisms through which the ɛ 4 allele contributes to disease pathophysiology are incompletely understood. The three common alleles of APOE , ɛ 2, ɛ 3 and ɛ 4, are defined by two single nucleotide polymorphisms (SNPs) that reside in the coding region of exon 4, which overlaps with a well-defined CpG island (CGI). Both SNPs change not only the protein codon but also the quantity of CpG dinucleotides, primary sites …for DNA methylation. Thus, we hypothesize that the presence of an ɛ 4 allele changes the DNA methylation landscape of the APOE CGI and that such epigenetic alteration contributes to AD susceptibility. To explore the relationship between APOE genotype, AD risk, and DNA methylation of the APOE CGI, we applied bisulfite pyrosequencing and evaluated methylation profiles of postmortem brain from 15 AD and 10 control subjects. We observed a tissue-specific decrease in DNA methylation with AD and identified two AD-specific differentially methylated regions (DMRs), which were also associated with APOE genotype. We further demonstrated that one DMR was completely un-methylated in a sub-population of genomes, possibly due to a subset of brain cells carrying deviated APOE methylation profiles. These data suggest that the APOE CGI is differentially methylated in AD brain in a tissue- and APOE -genotype-specific manner. Such epigenetic alteration might contribute to neural cell dysfunction in AD brain. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, CGI, CpG island, DMR, DNA methylation, epigenetics, pyrosequencing

DOI: 10.3233/JAD-143060

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 745-755, 2015

Authors: Matsuzono, Kosuke | Sato, Kota | Kono, Syoichiro | Hishikawa, Nozomi | Ohta, Yasuyuki | Yamashita, Toru | Deguchi, Kentaro | Nakano, Yumiko | Abe, Koji

Article Type: Research Article

Abstract: Background/Objective: Alzheimer’s disease (AD) is one of the most important diseases in an aging society, but the clinical effects of rivastigmine have not been fully examined in real world domestic clinics. Methods: We performed the “Okayama Rivastigmine Study (ORS)” to retrospectively analyze the clinical effects of rivastigmine (n  = 75) or donepezil (n  = 71) on AD patients with seven dementia assessment batteries at the baseline, 3, 6, and 12 months. In addition, we divided the rivastigmine group into two subgroups at the baseline: the mild behavioral and psychological symptoms of dementia (BPSD) group (Abe’s BPSD score …(ABS) <6) and the severe BPSD group (6≤ABS). In these two subgroups, baseline scores and changes were also retrospectively analyzed until 12 months. Results: Rivastigmine significantly improved the Mini-Mental State Examination score at 3 months (* p  <  0.05 versus baseline) and at 6 months (* p  <  0.05), the Frontal Assessment Battery (FAB) at 6 months (* p  <  0.05), and ABS at 3 months (** p  <  0.01) while donepezil only stabilized the three cognitive scores. On the other hand, the Geriatric Depression Scale and the Apathy Scale were stable until 12 months in both groups. Baseline BPSD severity-dependent analysis showed a small improvement of FAB at 6 months in the mild BPSD subgroup (* p  <  0.05) and a great improvement of ABS at 3 months in the severe BPSD subgroup (** p  <  0.01) in the rivastigmine group. Conclusions: Our present study showed that rivastigmine improved both cognitive and affective functions at 3 and 6 months, and suggested an advantage at 3 and 6 months compared to donepezil in real world dementia clinics. Show more

Keywords: Affective function, Alzheimer’s disease, cognitive function, donepezil, rivastigmine

DOI: 10.3233/JAD-150518

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 757-763, 2015

Authors: Pertl, Marie-Theres | Benke, Thomas | Zamarian, Laura | Delazer, Margarete

Article Type: Research Article

Abstract: Making advantageous decisions is important in everyday life. This study aimed at assessing how patients with mild cognitive impairment (MCI) make decisions under risk. Additionally, it investigated the relationship between decision making, ratio processing, basic numerical abilities, and executive functions. Patients with MCI (n  = 22) were compared with healthy controls (n  = 29) on a complex task of decision making under risk (Game of Dice Task-Double, GDT-D), on two tasks evaluating basic decision making under risk, on a task of ratio processing, and on several neuropsychological background tests. Patients performed significantly lower than controls on the GDT-D and on ratio processing, …whereas groups performed comparably on basic decision tasks. Specifically, in the GDT-D, patients obtained lower net scores and lower mean expected values, which indicate a less advantageous performance relative to that of controls. Performance on the GDT-D correlated significantly with performance in basic decision tasks, ratio processing, and executive-function measures when the analysis was performed on the whole sample. Patients with MCI make sub-optimal decisions in complex risk situations, whereas they perform at the same level as healthy adults in simple decision situations. Ratio processing and executive functions have an impact on the decision-making performance of both patients and healthy older adults. In order to facilitate advantageous decisions in complex everyday situations, information should be presented in an easily comprehensible form and cognitive training programs for patients with MCI should focus—among other abilities—on executive functions and ratio processing. Show more

Keywords: Aging, decision making, dementia, ratio processing

DOI: 10.3233/JAD-150291

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 765-779, 2015

Authors: Zhang, Sisi | Chen, Yaojing | Liu, Zhen | Zhang, Junying | Li, Xin | Cui, Ruixue | Zhang, Zhanjun

Article Type: Research Article

Abstract: The apolipoprotein E (APOE ) ɛ 4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). This study aimed to investigate abnormality of white matter integrity and its relationship to cognitive impairments in Chinese non-demented elderly with and without the ɛ 4 allele. We assessed cognitive differences using a series of neuropsychological tests and assessed white matter integrity using tract-based spatial statistics to measure mean diffusivity and fractional anisotropy. We determined that there were no statistically significant group differences in any neuropsychological measures. However, APOE ɛ 4 carriers without cognitive decline exhibited widespread disruption of the white …matter tracts in several areas, including the cingulum, fornix, corpus callosum, and corona radiate. Furthermore, a correlation analysis in ɛ 4 carriers indicated that disruption of the right fornix stria terminalis and the genu of the corpus callosum were positively associated with cognitive impairment, including memory, executive function, spatial processing, attention, and language. The present study reveals the deleterious effects of the ɛ 4 allele on white matter, and this damage may potentially serve as a biomarker in preclinical investigations. Our promising results encourage further investigation using a multidimensional longitudinal approach with larger samples. Show more

Keywords: Alzheimer’s disease, APOE ɛ4 allele, cognition, diffusion tensor imaging, tract-based spatial statistics, white matter

DOI: 10.3233/JAD-150357

Citation: Journal of Alzheimer's Disease, vol. 48, no. 3, pp. 781-791, 2015