Journal of Alzheimer's Disease - Volume 25, issue 3

Authors: Kelley, Christy M. | Perez, Sylvia E. | Overk, Cassia R. | Wynick, David | Mufson, Elliott J.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) plaques occur in close apposition to thickened or swollen cholinergic and galaninergic neurites within the neocortex and hippocampus in Alzheimer's disease (AD). Despite this observation, the effect of Aβ deposition upon cholinergic and galaninergic dystrophic neurite formation remains unclear. Therefore, the purpose of this study was to evaluate the interaction between Aβ deposition within the neocortex and hippocampus upon cholinergic and galaninergic dystrophic neurite formation. Neocortical and hippocampal tissue harvested from 3- and 12-month-old amyloid-β protein precursor (AβPP)swe /PS1ΔE9 transgenic (Tg) mice were dual-immunolabeled with antibodies against either choline acetyltransferace and Aβ (10D5) or galanin (Gal) and Aβ. …Stereology was used to quantify amyloid plaques and cholinergic or galaninergic dystrophic neurites. Plaque number was assessed using the optical fractionator; plaque area was calculated with the Cavalieri estimator, and dystrophic neurite numbers and thickness were manually measured. Neither amyloid nor dystrophic neuritic profiles were seen in the brains of 3-month-old Tg mice. In contrast, quantitative analysis revealed significantly more plaques in neocortex than hippocampus, with no difference in regional plaque size in 12-month-old Tg mice. Significantly more cholinergic than galaninergic dystrophic neurites-per-plaque occurred in the neocortex and hippocampus. Additionally, cholinergic dystrophic neurites were thicker than galaninergic dystrophic neurites in both regions. These data suggest that amyloid plaque deposition has a greater impact upon cholinergic than galaninergic dystrophic neurite formation in the neocortex and hippocampus in AβPPswe /PS1ΔE9 Tg mice. These data are also compatible with the hypothesis that galanin is neuroprotective and reduces dystrophic neurite formation in the face of amyloid toxicity. Show more

Keywords: Alzheimer's disease, amyloid, cholinergic, galanin, hippocampus, neocortex, neurites, plaques, transgenic mouse

DOI: 10.3233/JAD-2011-102097

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 491-504, 2011

Authors: Chalbot, Sonia | Zetterberg, Henrik | Blennow, Kaj | Fladby, Tormod | Andreasen, Niels | Grundke-Iqbal, Inge | Iqbal, Khalid

Article Type: Research Article

Abstract: The role of blood-cerebrospinal fluid barrier (BCB) dysfunction in Alzheimer's disease (AD) has been addressed but not yet established. We evaluated the BCB integrity in 179 samples of cerebrospinal fluid (CSF) retrospectively collected from AD patients and control cases using both CSF/serum albumin ratio (QAlb ) and CSF secretory Ca2+ -dependent phospholipase A2 (sPLA2) activity. These analyses were supplemented with the measurement of total tau, amyloid-β1-42 (Aβ1-42 ), and ubiquitin CSF levels. We found that due to its higher sensitivity, CSF sPLA2 activity could 1) discriminate AD from healthy controls and 2) showed BCB impairment in neurological control cases …while QAlb could not. Moreover, the CSF sPLA2 activity measurement showed that around half of the AD patients were characterized by a BCB impairment. The BCB dysfunction observed in AD was independent from Mini-Mental State Examination score as well as CSF levels of total tau, Aβ1-42 , and ubiquitin. Finally, the BCB dysfunction was not limited to any of the CSF biomarkers-based previously identified subgroups of AD. These results suggest that the BCB damage occurs independent of and probably precedes both Aβ and tau pathologies in a restricted subgroup of AD patients. Show more

Keywords: Albumin, Alzheimer's disease, cerebrospinal fluid, secretory phospholipase A2

DOI: 10.3233/JAD-2011-101959

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 505-515, 2011

Authors: Heo, Jae-Hyeok | Lee, Sang-Rae | Lee, Soon-Tae | Lee, Kyoung-Min | Oh, Jin-Hwan | Jang, Dong-Pyo | Chang, Kyu-Tae | Cho, Zang-Hee

Article Type: Research Article

Abstract: Intracerebroventricular injection of streptozotocin (icv-STZ) in rodents induces cellular and behavioral features mimicking Alzheimer's disease (AD). However, the effect of icv-STZ in terms of regional cerebral glucose metabolism has not yet been examined in vivo. Given that regionally specific hypometabolism of glucose is a consistent neuroimaging marker in early AD, we monitored 18F-deoxyglucose uptake using a high-resolution micro-PET after icv-STZ in non-human primates. Two cynomolgus monkeys (Macaca fascicularis) received STZ (2 mg/kg), and another two were given normal saline as controls, at the cerebellomedullary cistern (CM) three times (day 1, 7, and 14). FDG-PET, as well as MRI for structural …evaluation, was performed immediately before, six weeks after, and 12 weeks after the first icv injection. In the STZ group, FDG uptake decreased significantly in comparison to the pre-injection baseline, at the precuneus, the posterior cingulate, and medial temporal cortices. Increase in sulcal markings suggesting brain atrophy was observed by MRI at six weeks post-injection. The structural changes normalized at 12 weeks, but the reduced FDG uptake persisted at the same loci. The cortical distribution of glucose hypometabolism was similar to that at early stages of AD patients. The findings demonstrate that the effect of icv-STZ is regionally specific, lending further support for the method as a model of AD pathogenesis. Show more

Keywords: Alzheimer's disease, cynomolgus, streptozotocin-induced AD model

DOI: 10.3233/JAD-2011-102079

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 517-523, 2011

Authors: Arroyo-Anlló, Eva M. | Bellouard, Stéphanie | Ingrand, Pierre | Gil, Roger

Article Type: Research Article

Abstract: This study examines the impact of automatic/controlled access processes on the semantic network in 30 patients with Alzheimer's disease (AD). The AD group was compared with a control group using a battery of neuropsychological tests, a variation of Hodges's semantic testing battery, designed to assess semantic knowledge. The AD group had markedly lower scores than the normal group on each semantic test, but with a different degree of deterioration depending on the nature of the processes (controlled/automatic) in accessing the semantic network. AD patients had poorer performances on the explicit semantic tasks mainly involving controlled-process access (e.g., the WAIS Similarities …Subtest) than those involving mainly automatic-process access (e.g., the Verbal Automatism test). Analyses of confidence intervals allowed a gradient of impaired performances in increasing order to be elaborated: a) the Verbal Automatism test, b) the WAIS Vocabulary Subtest, c) the WAIS Information Subtest, d) the Letter Fluency Task, e) Naming as a Response to Definition, f) the Category Fluency Task, g) the WAIS Similarities Subtest, and h) the Oral Denomination 80 Test. The results of our study suggest that explicit semantic tasks needing passive or automatic processes to access semantic memory would be better preserved in AD. Show more

Keywords: Aging, cognition, dementia, memory, test

DOI: 10.3233/JAD-2011-110083

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 525-533, 2011

Authors: Manich, Gemma | Mercader, Clara | del Valle, Jaume | Duran-Vilaregut, Joaquim | Camins, Antoni | Pallàs, Mercè | Vilaplana, Jordi | Pelegrí, Carme

Article Type: Research Article

Abstract: The senescence accelerated mouse-prone 8 (SAMP8) strain of mice is an experimental model of accelerated senescence that has also been proposed as a model of Alzheimer's disease as it shares several features with this dementia. We have recently reported amyloid-β (Aβ) granules in the hippocampus of SAMP8 mice, which contain Aβ42 and Aβ40 peptides and other amyloid-β protein precursor fragments. These granules appear clustered mainly in the stratum radiatum of the CA1 region and increase in number and size with age. Here we performed several studies to examine whether the Aβ granules in the hippocampus of SAMP8 mice …contain other proteins characteristic of neuropathological aggregates, such as tau, MAP2, and α-synuclein. Moreover, we examined whether the Aβ granules in the hippocampus correspond to heparan sulphate proteoglycan (HSPG) positive granules previously described in this animal model. The results showed that Aβ granules correspond to the HSPG granular structures, being syndecan-2, a protein involved in the remodeling of dendritic spines, the type of HSPG found. Tau and MAP2, but not α-synuclein depositions, were also found in Aβ aggregates. Granules do not appear to have an astrocytic origin, since although some Aβ clusters are associated with astrocyte processes, most clusters are not. On the other hand, the presence of tau, MAP2, and NeuN in Aβ granules suggests a neuronal origin. As the components identified in Aβ granules are characteristic of the aggregates present in some neurodegenerative diseases, the SAMP8 model seems to be appropriate for the study of the processes involved in these pathologies. Show more

Keywords: Alzheimer's disease, amyloid-β, hippocampus, HSPG, MAP-2, SAMP8, syndecan, tau

DOI: 10.3233/JAD-2011-101713

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 535-546, 2011

Authors: Libeu, Clare Peters | Poksay, Karen S. | John, Varghese | Bredesen, Dale E.

Article Type: Research Article

Abstract: Alzheimer's disease-associated amyloid-β (Aβ) peptide is neurotoxic as an oligomer, but not as a monomer, by an unknown mechanism. We showed previously that Aβ interacts with the amyloid-β precursor protein (AβPP), leading to caspase cleavage and cell death induction. To characterize this structure and interaction further, we purified the extracellular domain of AβPP695 (eAβPP) and its complex with Aβ oligomers (AβOs) of varying sizes, and then performed small angle X-ray scattering (SAXS). In the absence of any Aβ, eAβPP was a compact homodimer with a tight association between the E1 and E2 domains. Dimeric Aβ oligomers induced monomerization of …eAβPP while larger oligomers also bound eAβPP but preserved the homodimer. Efficient binding of the larger oligomers correlated with the presence of prefibrillar oligomers, suggesting that the eAβPP binding is limited to a conformational subset of Aβ oligomers. Both forms of Aβ bound to eAβPP at the Aβ-cognate region and induced dissociation of the E1 and E2 domains. Our data provide the first structural evidence for Aβ-AβPP binding and suggest a mechanism for differential modulation of AβPP processing and cell death signaling by Aβ dimers versus conformationally-specific larger oligomers. Show more

Keywords: Alzheimer's disease, amyloid-β oligomers, amyloid-β protein precursor, small angle X-ray scattering

DOI: 10.3233/JAD-2011-101938

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 547-566, 2011

Authors: Castellani, Rudy J.

Article Type: Book Review

DOI: 10.3233/JAD-2011-110808

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 567-567, 2011

Article Type: Other

DOI: 10.3233/JAD-2011-110024

Citation: Journal of Alzheimer's Disease, vol. 25, no. 3, pp. 569-570, 2011