Journal of Alzheimer's Disease - Volume 43, issue 1

Authors: Maté, Ianire | Cruces, Julia | Giménez-Llort, Lydia | De la Fuente, Mónica

Article Type: Research Article

Abstract: The aging process involves the impairment of the immune system (immunosenescence), based on the imbalance of the redox status, as occurs in neurodegenerative diseases such as Alzheimer's disease (AD). Since in AD there is a systemic disorder, we aimed to assess longitudinally, from before the onset until the complete establishment of AD, cell populations, several functions, and oxidative stress parameters in peritoneal leukocytes of triple transgenic mice for AD (3xTgAD). These animals mimic the human AD pathophysiology. The results indicate a premature immunosenescence in 3xTgAD at 4 months of age, when the immunoreactivity against intracellular amyloid-β fibrils appears. Thus, decreases …in functions such as chemotaxis, phagocytosis, and lymphoproliferation, as well as a lower reduced glutathione content and higher xanthine oxidase activity, appear in leukocytes. Moreover, NK percentage and cytotoxic activity, CD25+ B and naïve CD8 T cells percentage, GSSG/GSH ratio, and GSH content were already changed before the onset of AD, at the age of 2 months. Furthermore, the changes in some parameters such as CD5+ B1 cells, phagocytosis, lymphoproliferation, and xanthine oxidase activity continue at 15 months of age, when AD pathophysiology is completely established. Because the immune system parameters studied are markers of health and longevity, the premature immunosenescence could explain the shorter life span shown by 3xTgAD observed in the present work. These results suggest that peripheral immune cell functions and their oxidative stress status could be good early peripheral markers of the preclinical and prodromal stages and progression of AD. Show more

Keywords: Immune function, immunosenescence, oxidative stress, peritoneal leukocytes, 3xTgAD

DOI: 10.3233/JAD-140861

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 213-226, 2015

Authors: Peng, Lei | Yu, Yang | Liu, Jin | Li, Shuqin | He, Huiqiong | Cheng, Ni | Ye, Richard D.

Article Type: Research Article

Abstract: Amyloid-β peptides such as Aβ1-42 (Aβ42 ) play a pivotal role in the progression of Alzheimer's disease (AD). Aβ42 is neurotoxic and can activate microglial cells. These cells in turn migrate toward senile (neuritic) plaques and help to clear Aβ deposits through an endocytotic mechanism. It is of potential significance to characterize the Aβ42 receptors that mediate microglia chemotaxis and Aβ42 uptake. We found that the transcript of the chemerin receptor CMKLR1 was upregulated in the brain of AD patients and in mouse brain tissue following systemic LPS administration. CMKLR1 and Aβ42 colocalized in hippocampus …and cortex of AβPP/PS1 transgenic mice. Moreover, Aβ42 bound specifically to CMKLR1 in stably transfected rat basophilic leukemia (RBL) cells (CMKLR1-RBL), suggesting that CMKLR1 is a receptor for Aβ42 . Aβ42 induced migration of primary microglia, the mouse microglial cell line N9, and CMKLR1-RBL cells, but not untransfected RBL-2H3 cells. Mechanistic studies showed that Aβ42 induced CMKLR1-dependent cell migration through activation of the ERK1/2, PKA, and Akt pathways, but not Ca2+ mobilization. Aβ42 stimulation of CMKLR1-RBL cells and primary glial cells led to internalization of the Aβ42 -CMKLR1 complex, suggesting a potential role for CMKLR1 in Aβ42 clearance. Taken together, these results indicate that Aβ42 activates CMKLR1, leading to glia cell migration and clearance of Aβ42 . CMKLR1 is a new addition to the repertoire of cell surface molecules that are responsible for Aβ processing and clearance. Show more

Keywords: Alzheimer's disease, amyloid-β, chemerin receptor, chemotaxis, microglial cells

DOI: 10.3233/JAD-141227

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 227-242, 2015

Authors: Uhm, Kyung-Ok | Kim, Mi-Jeong | Kawaguchi, Makoto | Akatsu, Hiroyasu | Miura, Yutaka | Misumi, Sachiyo | Hida, Hideki | Choi, Eun-Kyoung | Kim, Yong-Sun | Michikawa, Makoto | Jung, Cha-Gyun

Article Type: Research Article

Abstract: The cytoplasmic C-terminal domain of amyloid-β protein precursor (AβPP) binds to several proteins that regulate the trafficking and processing of AβPP and affects amyloid-β (Aβ) production. We previously reported that levels of AT-motif binding factor 1 (ATBF1) are increased in the brains of 17-month-old Tg2576 mice compared with wild-type controls, and that Aβ42 increases ATBF1 expression, inducing death in primary rat cortical neurons. Here, we show that ATBF1 levels are increased in the cytoplasm of hippocampal neurons in Alzheimer's disease (AD) brains compared with non-AD brains. Furthermore, cotransfection of human embryonic kidney (HEK293T) and human neuroblastoma (SH-SY5Y) cells with …ATBF1 and AβPP695 increased steady-state levels of AβPP via the binding of ATBF1 to the AβPP cytoplasmic domain (amino acids 666–690), resulting in increased Aβ production and cellular and soluble AβPP (sAβPP) levels without affecting the activity or levels of AβPP processing enzymes (α-, β-, or γ-secretase). Conversely, knockdown of endogenous ATBF1 reduced levels of cellular AβPP, sAβPP, and Aβ in HEK293 cells overexpressing human AβPP695. Our findings provide insight into the dynamics of AβPP processing and Aβ production, and suggest that ATBF1 is a novel AβPP binding protein that may be a suitable therapeutic target for AD. Show more

Keywords: Aβ production, AβPP binding protein, AβPP stabilization, Alzheimer's disease, ATBF1

DOI: 10.3233/JAD-140612

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 243-257, 2015

Authors: Cuesta, Pablo | Barabash, Ana | Aurtenetxe, Sara | Garcés, Pilar | López, María Eugenia | Bajo, Ricardo | Llanero-Luque, Marcos | Ancín, Inés | Cabranes, José Antonio | Marcos, Alberto | Sancho, Miguel | Nakamura, Akinori | Maestú, Fernando | Fernandez, Alberto

Article Type: Research Article

Abstract: The apolipoprotein E (APOE) ε4 allele is a genetic risk factor for the development of late-onset Alzheimer's disease (AD), which affects cholinergic system functioning. The association between reduced cholinergic levels and increase of magnetoencephalographic (MEG) low-frequency has been used to explain spectral changes found in AD patients. However, the investigation in predementia stages is scarce. We obtained MEG recordings from 25 aged controls and 36 mild cognitive impairment (MCI) patients during a resting-state condition. According to their APOE genotype, MCIs and controls were subdivided in carriers and non-carriers of the ε4 allele. Sources of spectral variations in these groups were …calculated through beamforming. MCI patients exhibited a significant increase of relative power within the low-frequency domain, accompanied by a power decrease within the high-frequency range. APOEε4 carriers showed an increased relative power in the 4.5–6.5 Hz frequency range over frontal lobes. The power increase observed in controls carrying ε4 was significantly higher as compared with MCI non-carriers, while MCI carriers exhibited the highest relative power within the 4.5–6.5 Hz range. Higher power values within the low-frequency ranges correlated with a poorer cognitive performance in MCIs and controls. Our investigation demonstrates that APOEε4 affects resting-state activity to an extent that makes it more proximate to the pattern observed in early stages of AD. Therefore, a combination of genetic and neurophysiological information might help to detect MCI patients at higher risk of conversion to AD, and asymptomatic subjects at higher risk of developing a manifest cognitive deterioration. Show more

Keywords: Aging, APOEε4, magnetoencephalography, mild cognitive impairment, relative power, source analysis

DOI: 10.3233/JAD-140633

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 259-273, 2015

Authors: Royall, Donald R. | Palmer, Raymond F. | for the Texas Alzheimer's Research and Care Consortium

Article Type: Research Article

Abstract: We have employed structural equation models to explicitly distinguish functional status, and therefore “dementia-relevant” variance in cognitive task performance (i.e., “δ”). We previously associated δ with cytokines and other serum biomarkers in a well characterized Alzheimer's disease cohort, the Texas Alzheimer's Research and Care Consortium. However, that δ homolog did not exhibit factor equivalence across ethnicity. In this study, we construct a δ homolog that exhibits mean and factor equivalence across ethnicity [i.e., “d(=)”]. d(=) is associated significantly with ten of the twelve previously selected biomarkers. Most of these associations are again specific to Non-Hispanic White participants. These findings have …yet to be validated in other cohorts, but may suggest cross-ethnic differences in dementia's pathobiological mechanisms between Hispanic Mexican-Americans and Non-Hispanic Whites. Show more

Keywords: Aging, cognition, dementia, functional status, g, Hispanic

DOI: 10.3233/JAD-140264

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 275-287, 2015

Authors: Balsis, Steve | Lowe, Deborah A.

Article Type: Article Commentary

Abstract: The paper, “Ethnicity Moderates Dementia's Biomarkers”, by Royall and Palmer in this issue of Journal of Alzheimer's Disease represents the cutting edge of Alzheimer's disease (AD) research. The authors capitalize on several powerful and emerging trends in AD research that will surely reap benefits for our discipline during the next decade: latent variable models, biomarkers, and ethnicity. In this study, the authors specifically find that self-reported ethnicity moderates the dementing process and hypothesize that this is more likely due to distinct biological mechanisms than environmental influences.

Keywords: Aging, cognition, dementia, ethnicity, Hispanic, TARCC

DOI: 10.3233/JAD-141161

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 289-290, 2015

Authors: Yu, Dan | Tao, Bang-Bao | Yang, Yun-Yun | Du, Li-Sha | Yang, Shuang-Shuang | He, Xiao-Jie | Zhu, Yu-Wen | Yan, Jun-Kai | Yang, Qing

Article Type: Research Article

Abstract: Indoleamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan catabolism, was recently established as one of the potential players involved in the pathogenesis of Alzheimer's disease (AD). Coptisine is a main pharmacological active constituent of the traditional Chinese medicinal prescription Oren-gedoku-to (OGT) which has therapeutic potential for the treatment of AD. Our recent studies have demonstrated that OGT significantly inhibited recombinant human IDO activity, which shed light on the possible mechanism of OGT's action on AD. Here, we characterized the effects of coptisine in an AD mouse model on the basis of its IDO …inhibitory ability. Coptisine was found to be an efficient uncompetitive IDO inhibitor with a Ki value of 5.8 μM and an IC50 value of 6.3 μM. In AβPP/PS1 transgenic mice, oral administration of coptisine inhibited IDO in the blood and decreased the activation of microglia and astrocytes, consequently prevented neuron loss, reduced amyloid plaque formation, and ameliorated impaired cognition. Neuronal pheochromocytoma (PC12) cells induced with amyloid-β peptide 1–42 and interferon-γ showed reduction of cell viability and enhancement of IDO activity, while coptisine treatment increased cell viability based on its reversal effect on the enhanced activity of IDO. In conclusion, our present findings provide further evidence supporting the critical links between IDO, KP, and AD, and demonstrate coptisine, a novel IDO inhibitor, as a potential new class of drugs for AD treatment. Show more

Keywords: Alzheimer's disease, coptisine, indoleamine 2, 3-dioxygenase, indoleamine 2, 3-dioxygenase inhibitor, kynurenine pathway

DOI: 10.3233/JAD-140414

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 291-302, 2015

Authors: Chiam, Justin Tao Wen | Dobson, Richard James Butler | Kiddle, Steven John | Sattlecker, Martina

Article Type: Research Article

Abstract: Background: Alzheimer's disease (AD) biomarkers are urgently needed for both early and accurate diagnosis and prediction of disease progression. Past research has studied blood-based proteins as potential AD biomarkers, revealing many candidate proteins. To date only limited effort has been made to investigate the disease specificity of AD candidate proteins and whether these proteins are also involved in other neurodegenerative or psychiatric conditions. Objective: This review seeks to determine if blood-based AD candidate protein biomarkers are disease specific. Methods: A two-stage systematic literature search was conducted. Firstly, the most consistently identified AD protein biomarkers in blood …were determined from a list of published discovery or panel-based (>100 proteins) blood proteomics studies in AD. Secondly, an online database search was conducted using the 10 most consistently identified proteins to determine if they were involved in other brain disorders, namely frontotemporal lobe dementia, vascular dementia, Lewy body disease, Parkinson's disease, schizophrenia, depression, and autism. Results: Among the reviewed candidate proteins, plasma protease C1 inhibitor, pancreatic prohormone, and fibrinogen γ chain were found to have the least evidence for non-specificity to AD. All other candidates were found to be affected by other brain disorders. Conclusion: Since we found evidence that the majority of AD candidate proteins might also be involved in other brain disorders, more research into the disease specificity of AD protein biomarkers is required. Show more

Keywords: Alzheimer's disease biomarker, autism, blood, cross-disorder comparison, depression, other types of dementia, Parkinson's disease, proteins, schizophrenia

DOI: 10.3233/JAD-140816

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 303-314, 2015

Authors: Seifan, Alon | Marder, Karen S. | Mez, Jesse | Noble, James M. | Cortes, Etty P. | Vonsattel, Jean Paul | Honig, Lawrence S.

Article Type: Research Article

Abstract: Background: Cerebral deposition of phospho-tau in Alzheimer's disease (AD) occurs with varying patterns within hippocampus. Lamina-specific tau changes in AD may reflect trans-synaptic propagation of phospho-tau along neuroanatomical pathways. Objective: To study patterns of tau deposition within inner (IML) and outer (OML) molecular layers of dentate gyrus and their clinical and neuropathological correlates. Methods: 98 consecutive autopsied brains from the Columbia University Brain Bank were stained for phospho-tau using AT-8. Staining density was rated as High versus Low within IML and OML. Four patterns were observed among the 98 brains: High IML&OML, n = 44; High …OML Only (n = 35); High IML Only (n = 5); and Low IML&OML (n = 14). Demographic, clinical, and neuropathological characteristics of these four groups were compared. Results: High IML&OML subjects, versus High OML Only, were more likely to fulfill CERAD criteria for Definite AD (93% versus 66%, p < 0.01) and to have higher median Braak stage (6 versus 5, p < 0.01) and earlier mean age of onset (65.9 versus 73.7 y, p = 0.02), with similar symptom duration. Using logistic regression, the association between High IML&OML and AD remained significant after adjustment for demographics but not symptom duration. In the 70 subjects with Definite AD, High IML&OML was associated with younger age of onset (mean difference 3.7 years, 95%CI −6.7 to −0.7, p < 0.01), after adjustment for demographics and symptom duration. Conclusions: Phospho-tau pathology, when prominent within both IML and OML, is associated with CERAD diagnosis of Definite AD and earlier age of onset in AD. Laminar patterns of tau deposition reflect regional involvements during disease course. Show more

Keywords: Alzheimer's disease, dentate gyrus, hippocampus, perforant pathway, tau proteins

DOI: 10.3233/JAD-140279

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 315-324, 2015

Authors: Hernández, Isabel | Rosende-Roca, Maitée | Alegret, Montserrat | Mauleón, Ana | Espinosa, Ana | Vargas, Liliana | Sotolongo-Grau, Oscar | Tárraga, Lluís | Boada, Mercè | Ruiz, Agustín

Article Type: Research Article

Abstract: Transmembrane Protein 106B SNP rs1990622 was recently shown to modify the risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTD-TDP). An independent replication study of this genetic variant was performed in 381 individuals from Catalonia (Spain). By applying a recessive model, a tendency toward an association with FTD risk was observed in our case-control study (age- and gender-adjusted odds ratio = 0.57; p = 0.082). Importantly, meta-analysis of available studies also supports a recessive effect for rs1990622 CC genotype (OR = 0.70; CI 95% [0.57–0.85]; p = 0.0003) and demonstrates the existence of statistical heterogeneity due to an inherent pathological …heterogeneity between series (p = 0.00014). We conclude that TMEM106B is associated with FTD, although the extent of this effect is difficult to be estimated by using clinical FTD series. Show more

Keywords: Frontotemporal dementia, genetics, genome-wide association study, molecular epidemiology, TMEM106B

DOI: 10.3233/JAD-132432

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 325-334, 2015

Article Type: Correction

DOI: 10.3233/JAD-159000

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 335-335, 2015

Article Type: Other

DOI: 10.3233/JAD-141399

Citation: Journal of Alzheimer's Disease, vol. 43, no. 1, pp. 337-339, 2015