Journal of Alzheimer's Disease - Volume 37, issue 4

Authors: Chaunu, Marie-Pierre | Deramecourt, Vincent | Buée-Scherrer, Valérie | Le Ber, Isabelle | Brice, Alexis | Ehrle, Nathalie | El Hachimi, Khalid | Pluot, Michel | Maurage, Claude-Alain | Bakchine, Serge | Buée, Luc

Article Type: Research Article

Abstract: Frontotemporal lobe degeneration includes a large spectrum of neurodegenerative disorders. Patients with frontotemporal dementia with parkinsonism linked to chromosome 17 exhibit heterogeneity in both clinical and neuropathological features. Here, we report the case of a young patient with a G389R mutation. This teenager girl was 17 years old when she progressively developed severe behavioral disturbances. First, she was considered to be suffering from atypical depression. After 2 years, she was referred to the department of neurology. By this time, the patient exhibited typical frontotemporal dementia with mild extrapyramidal disorders. The main behavioral features included apathy and reduced speech output. MRI …and SPECT showed a frontotemporal atrophy and hypofixation, respectively. She died 7 years after onset. Three relatives on her father side had also died after early onset dementia. Genetic testing revealed a heterozygous guanine to cytosine mutation at the first base of codon 389 (Exon 13) of MAPT, the tau gene, resulting in a glycine to arginine substitution, in the patient and her non-affected father. Postmortem neuropathological and biochemical data indicate a Pick-like tau pathology but with phosphoserine 262-positive immunoreactivity. This case is remarkable because of the extremely early onset of the disease. Show more

Keywords: Early onset dementia, frontotemporal lobar degeneration, G389R mutation, MAPT, Pick bodies, tau protein

DOI: 10.3233/JAD-130413

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 769-776, 2013

Authors: Van der Jeugd, Ann | Vermaercke, Ben | Derisbourg, Maxime | Lo, Adrian C. | Hamdane, Malika | Blum, David | Buée, Luc | D'Hooge, Rudi

Article Type: Research Article

Abstract: Age-related cognitive decline and neurodegenerative diseases are a growing challenge for society. Accumulation of tau pathology has been proposed to partially contribute to these impairments. This study provides a behavioral characterization during aging of transgenic mice bearing tau mutations. THY-Tau22 mice were evaluated at ages wherein tau neuropathology in this transgenic mouse model is low (3-4 months), moderate (6-7 months), or extensive (>9 months). Spatial memory was found to be impaired only after 9 months of age in THY-Tau22 mice, whereas non-spatial memory was affected as early as 6 months, appearing to offer an opportunity for assessing potential therapeutic agents …in attenuating or preventing tauopathies through modulation of tau kinetics. Show more

Keywords: aging, learning, memory, tauopathy, transgenic model

DOI: 10.3233/JAD-130110

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 777-788, 2013

Authors: Chamard, Ludivine | Wallon, David | Pijoff, Alexa | Berger, Eric | Viennet, Gabriel | Hannequin, Didier | Magnin, Eloi

Article Type: Research Article

Abstract: Immune response to vascular amyloid-β deposits leads to cerebral amyloid angiopathy related-inflammation (CAA-ri). Amyloid-related imaging abnormalities (ARIA) were initially reported during anti-amyloid trials and are associated with the APOE 4/4 genotype. We report the evolution of an AβPP duplication carrier with an APOE 3/3 genotype presenting ARIA-Effusion and then ARIA-Hemosiderin deposit, without anti-amyloid therapy, suggestive of a possible spontaneously resolutive CAA-ri (not neuropathologically proven). It suggests common mechanisms between ARIA and CAA-ri and raises questions about mechanisms of this acute episode without APOE risk factor. The high vascular amyloid burden, induced by AβPP duplication, might increase amyloid epitope presentation and …lead to inflammatory process. Show more

Keywords: AβPP duplication, Alzheimer's disease, amyloid burden, APOE, cerebral amyloid angiopathy-related inflammation

DOI: 10.3233/JAD-130629

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 789-793, 2013

Authors: Duan, Dong-Xiao | Chai, Gao-Shang | Ni, Zhong-Fei | Hu, Yu | Luo, Yu | Cheng, Xiang-Shu | Chen, Ning-Ning | Wang, Jian-Zhi | Liu, Gong-Ping

Article Type: Research Article

Abstract: The intracellular accumulation of hyperphosphorylated tau plays a crucial role in neurodegeneration of Alzheimer's disease (AD), but the mechanism is not fully understood. From the observation that tau hyperphosphorylation renders cells more resistant to chemically-induced cell apoptosis, we have proposed that tau-involved apoptotic abortion may be the trigger of neurodegeneration. Here, we further studied whether this phenomenon is also applicable for the cell death induced by constitutively expressed factors, such as death-associated protein kinase 1 (DAPK1). We found that DAPK1 was upregulated and accumulated in the brain of human tau transgenic mice. Overexpression of DAPK1 in HEK293 and N2a cells …decreased cell viability with activation of caspase-3, whereas simultaneous expression of tau antagonized DAPK1-induced apoptotic cell death. Expression of DAPK1 induced tau hyperphosphorylation at Thr231, Ser262, and Ser396 with no effects on protein phosphatase 2A, glycogen synthase kinase-3β, protein kinase A, calcium/calmodulin dependent protein kinase II, cell division cycle 2, or cyclin dependent protein kinase 5. The phosphorylation level of microtubule affinity-regulating kinase 2 (MARK2) was increased by expression of DAPK1, but simultaneous downregulation of MARK2 did not affect the DAPK1-induced tau hyperphosphorylation. DAPK1 was co-immunoprecipitated with tau proteins both in vivo and in vitro, and expression of the kinase domain-truncated DAPK1 did not induce tau hyperphosphorylation. These data suggest that tau hyperphosphorylation at Thr231, Ser262, and Ser396 by DAPK1 renders the cells more resistant to the kinase-induced apoptotic cell death, providing new insights into the tau-involved apoptotic abortion in the course of chronic neurodegeneration. Show more

Keywords: Alzheimer's disease, apoptosis, death-associated protein kinase 1 (DAPK1), tau phosphorylation

DOI: 10.3233/JAD-130377

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 795-808, 2013

Authors: Fox, Molly | Berzuini, Carlo | Knapp, Leslie A.

Article Type: Research Article

Abstract: The effect of early and midlife factors on later-life cognitive function has attracted scientific and public interest in recent years, especially with respect to hormonal risk factors for dementia. There is substantial evidence for reproductive history affecting Alzheimer's disease (AD) etiology. Here, we demonstrate how breastfeeding history affects women's risk of AD. Reproductive history data was collected, and AD diagnostic interviews were performed, for a cohort of elderly British women. Using Cox proportional-hazard models, we find that longer breastfeeding duration corresponded to reduced risk of AD (p < 0.01, n = 81). Women who breastfed had lower AD risk than …women who did not breastfeed (p = 0.017, n = 81). Breastfeeding practices are an important modifier of cumulative endogenous hormone exposure for mothers. Ovarian hormone deprivation and/or insulin sensitivity benefits of breastfeeding may be responsible for the observed reduction in AD risk. Future studies concerning hormone effects on AD risk should consider how reproductive history leads to variation in endogenous hormone exposure and how this may influence the relationship between hormones and AD. Show more

Keywords: Alzheimer's disease, breastfeeding, estrogen, hormones, lactation, reproductive history, risk factors

DOI: 10.3233/JAD-130152

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 809-821, 2013

Authors: Cheng, Xiaorui | Zhou, Yu | Gu, Wei | Wu, Jie | Nie, Aihua | Cheng, Junping | Zhou, Jinwu | Zhou, Wenxia | Zhang, Yongxiang

Article Type: Research Article

Abstract: β-site amyloid-β protein precursor cleaving enzyme 1 (BACE1) is the first protease and the rate limiting enzyme in the genesis of amyloid-β (Aβ). This protein remains an important potential disease-modifying target for the development of drugs to treat Alzheimer's disease (AD). We are pursuing potent BACE1 inhibitors in an effort to identify suitable AD drug candidates. Our results have shown that the novel compound VIa exhibits potent inhibitory effects with IC50 = 5.9 nM and displays 30.8-fold, 7500-fold and 17533-fold selectivity against the other aspartic proteases BACE2, cathepsin D and renin, respectively. In cellular assays, VIa moderately reduces Aβ …production: Aβ1-40 with an IC50 = 143 nM and 1 nM VIa reduced Aβ1-42 by 40.17%. Concomitant with VIa inhibiting the β-cleavage of amyloid-β protein precursor (AβPP), VIa increases the production of sAβPPα with an approximate EC50 of 16.5 nM. In testing this compound's efficacy in vivo, the oral administration of VIa resulted in a significant decrease in Aβ1-40 and Aβ1-42 in the blood of a mouse model of AD by 17.5–72.44% and 14.5–80.32%, respectively. This indicates that the novel compound VIa is a small, potent, selective, and non-peptidic BACE1 inhibitor. Show more

Keywords: Alzheimer's disease, amyloid-β, β-site AβPP cleaving enzyme 1, inhibitor

DOI: 10.3233/JAD-130836

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 823-834, 2013

Authors: Nguyen, Huey T. | Sawmiller, Darrell R. | Markov, Olga | Chen, Ming

Article Type: Research Article

Abstract: Elevated intracellular Ca2+ levels in the aging brain are widely thought to hyperactivate Ca2+ signaling and Ca2+ -dependent enzymes, leading to neuronal death through an excitatory mechanism in Alzheimer's disease (AD). This “Ca2+ overload” hypothesis has been questioned by our theoretical analyses. To better understand the relationship between the “level” and functionality of Ca2+ in aging, in this study we simultaneously measured intracellular Ca2+ transients and calpain activity in cultured human fibroblasts. We found that Ca2+ transitions elicited by bradykinin were indeed overstayed or elevated in levels in old cells but, remarkably, calpain activity …was decreased compared to young cells. Also, treating young cells with the energy inhibitor rotenone or with H2 O2 recapitulated the Ca2+ overstay and calpain inactivation found in old cells. More importantly, treating old cells with high-energy compounds such as phosphoenol pyruvate or phosphocreatine, which boosted cellular ATP content, reduced the Ca2+ overstay and re-activated calpain. Moreover, Ca2+ levels and calpain activity were dramatically raised in the dying cells killed by detergent. Finally, Ca2+ oscillations induced by low dose of bradykinin in old cells exhibited lower spike frequency, but higher overall levels. Collectively, these results suggest that (a) Ca2+ overload in old cells arises from an inefficient Ca2+ handling system compromised by age-related energy depletion and oxidative stress; and (b) despite elevated levels, the functionality of Ca2+ signaling has diminished in old cells. Thus, the study reinforces the concept that tonic promotion of bioenergetics and Ca2+ signaling function is a reasonable and new paradigm to protect the aging brain cells to prevent AD. Show more

Keywords: Alzheimer's disease, calcium, calpain, energy

DOI: 10.3233/JAD-131001

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 835-848, 2013

Authors: Morales, Inelia | Jiménez, José M. | Mancilla, Marcela | Maccioni, Ricardo B.

Article Type: Research Article

Abstract: Neuroinflammation is a process related to the onset of several neurodegenerative disorders, including Alzheimer's disease (AD). Increasing sets of evidence support the major role of deregulation of the interaction patterns between glial cells and neurons in the pathway toward neuronal degeneration, a process we are calling neuroimmunomodulation in AD. On the basis of the hypothesis that pathological tau aggregates induce microglial activation with the subsequent events of the neuroinflammatory cascade, we have studied the effects of tau oligomeric species and filamentous structures over microglial cells in vitro. Tau oligomers and fibrils were induced by arachidonic acid and then their actions …assayed upon addition to microglial cells. We showed activation of the microglia, with significant morphological alterations as analyzed by immunofluorescence. The augmentation of nitrites and the proinflammatory cytokine IL-6 was evaluated in ELISA assays. Furthermore, conditioned media of stimulated microglia cells were exposed to hippocampal neurons generating altered patterns in these cells, including shortening of neuritic processes and cytoskeleton reorganization. Show more

Keywords: Alzheimer's disease, glial cells, neuroinflammation, tau aggregates

DOI: 10.3233/JAD-131843

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 849-856, 2013

Authors: Kim, Jinho | Jeong, Yong

Article Type: Research Article

Abstract: Based on enlarged blood oxygen level-dependent (BOLD) responses in cognitively normal subjects at risk for Alzheimer's disease (AD), compensatory neuronal hyperactivation has been proposed as an early marker for diagnosis of AD. The BOLD response results from neurovascular coupling, i.e., hemodynamic response induced by neuronal activity. However, there has been no evidence of task-induced increases in hemodynamic response in animal models of AD. Here, we observed an augmented hemodynamic response pattern in a transgenic AβPPSWE /PS1ΔE9 mouse model of AD using three in vivo imaging methods: intrinsic optical signal imaging, multi-photon laser scanning microscopy, and laser Doppler flowmetry. Sensory stimulation …resulted in augmented and prolonged hemodynamic responses in transgenic mice evidenced by changes in total, oxygenated, and deoxygenated hemoglobin concentration. This difference between transgenic and wild-type mice was significant at 7 months of age when amyloid plaques and cerebral amyloid angiopathy had developed but not at younger or older ages. Correspondingly, sensory stimulation-induced pial arteriole diameter was also augmented and prolonged in transgenic mice at 7 months of age. Cerebral blood flow response in transgenic mice was augmented but not prolonged. These results are consistent with the existence of BOLD signal hyperactivation in non-demented AD-risk human subjects, supporting its potential use as an early diagnostic marker of AD. Show more

Keywords: Alzheimer's disease, cerebral amyloid angiopathy, functional brain imaging, multiphoton fluorescence microscopy

DOI: 10.3233/JAD-121900

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 857-868, 2013

Article Type: Other

DOI: 10.3233/JAD-130910

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 869-875, 2013

Article Type: Other

DOI: 10.3233/JAD-131002

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 877-879, 2013

Article Type: Other

DOI: 10.3233/JAD-2013-37422

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 881-889, 2013