Journal of Alzheimer's Disease - Volume 27, issue 2

Authors: Schweinzer, Cornelia | Kober, Alexandra | Lang, Ingrid | Etschmaier, Karoline | Scholler, Monika | Kresse, Adelheid | Sattler, Wolfgang | Panzenboeck, Ute

Article Type: Research Article

Abstract: Impaired clearance of cerebral amyloid-β (Aβ) across the blood-brain barrier (BBB) may facilitate the onset and progression of Alzheimer's disease (AD). Additionally, experimental evidence suggests a central role for cellular cholesterol in amyloid-β protein precursor (AβPP) processing. The present study investigated whether brain capillary endothelial cells (BCEC; the anatomical basis of the BBB) are capable of endogenous AβPP synthesis and whether and to what extent AβPP synthesis and processing is under control of cellular cholesterol homeostasis. Intracellular cholesterol metabolism was pharmacologically manipulated by using natural and synthetic liver-X receptor (LXR) agonists. Using an in vitro model of the BBB consisting …of primary porcine BCEC (pBCEC), we demonstrate that endogenous full-length AβPP synthesis by pBCEC is significantly increased while the amount of cell-associated, amyloidogenic Aβ oligomers is decreased in response to 24(S)-hydroxycholesterol (24OH-C) or 27OH-C, TO901317, cholesterol, or simvastatin treatment. Oxysterols, as well as simvastatin, enhanced the secretion of non-amyloidogenic sAβPPα up to 2.5-fold. In parallel, LXR agonists reduced cholesterol biosynthesis by 30–80% while stimulating esterification (up to 2.5-fold) and efflux (up to 2.5-fold) of cellular cholesterol by modifying hydroxymethylglutaryl-CoA reductase (HMGCR), sterol regulatory element-binding protein (SREBP-2), acyl-CoA: cholesterol acyltransferase 2 (ACAT-2), and ATP binding cassette transporter A1 (ABCA1) expression levels. In a polarized in vitro model mimicking the BBB, pBCEC secreted sAβPPα preferentially to the basolateral compartment. In summary endothelial cells of the BBB actively synthesize AβPP, Aβ oligomers, and secrete AβPPα in a polarized manner. AβPP processing by pBCEC is regulated by LXR agonists, which have been proven beneficial in experimental AD models. Show more

Keywords: Alzheimer's disease, amyloid-β, blood-brain barrier, cholesterol, endothelial cells, liver-X receptors, oxysterols, statins

DOI: 10.3233/JAD-2011-110854

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 341-360, 2011

Authors: Hunter, Jesse M. | Bowers, William J. | Maarouf, Chera L. | Mastrangelo, Michael A. | Daugs, Ian D. | Kokjohn, Tyler A. | Kalback, Walter M. | Luehrs, Dean C. | Valla, Jon | Beach, Thomas G. | Roher, Alex E.

Article Type: Research Article

Abstract: Transgenic (Tg) mouse models of Alzheimer's disease (AD) have been genetically altered with human familial AD genes driven by powerful promoters. However, a Tg model must accurately mirror the pathogenesis of the human disease, not merely the signature amyloid and/or tau pathology, as such hallmarks can arise via multiple convergent or even by pathogenic mechanisms unrelated to human sporadic AD. The 3 × Tg-AD mouse simultaneously expresses 3 rare familial mutant genes that in humans independently produce devastating amyloid-β protein precursor (AβPP), presenilin-1, and frontotemporal dementias; hence, technically speaking, these mice are not a model of sporadic AD, but are …informative in assessing co-evolving amyloid and tau pathologies. While end-stage amyloid and tau pathologies in 3 × Tg-AD mice are similar to those observed in sporadic AD, the pathophysiological mechanisms leading to these lesions are quite different. Comprehensive biochemical and morphological characterizations are important to gauge the predictive value of Tg mice. Investigation of AβPP, amyloid-β (Aβ), and tau in the 3 × Tg-AD model demonstrates AD-like pathology with some key differences compared to human sporadic AD. The biochemical dissection of AβPP reveals different cleavage patterns of the C-terminus of AβPP when compared to human AD, suggesting divergent pathogenic mechanisms. Human tau is concomitantly expressed with AβPP/Aβ from an early age while abundant extracellular amyloid plaques and paired helical filaments are manifested from 18 months on. Understanding the strengths and limitations of Tg mouse AD models through rigorous biochemical, pathological, and functional analyses will facilitate the derivation of models that better approximate human sporadic AD. Show more

Keywords: Alzheimer's disease, amyloid-β precursor protein, presenilin, tau, transgenic mice

DOI: 10.3233/JAD-2011-110608

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 361-376, 2011

Authors: Aerts, Marjolein B. | Esselink, Rianne A.J. | Claassen, Jugen A.H.R. | Abdo, Wilson Farid | Bloem, Bastiaan R. | Verbeek, Marcel M.

Article Type: Research Article

Abstract: Differentiating dementia with Lewy bodies (DLB) from Alzheimer's Disease (AD) can be difficult because of the substantial overlap in clinical features. Since deficits in serotonergic and dopaminergic pathways seem more pronounced in DLB patients, we investigated whether cerebrospinal fluid (CSF) analysis of neurotransmitter metabolites, in addition to brain-specific proteins, may improve the differentiation between DLB and AD. We retrospectively compared CSF concentrations of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) and the brain-specific proteins total tau (t-tau), phosphorylated tau protein (p-tau), and amyloid-β42 (Aβ42 ) in 45 patients with AD (mean age 71.6 years; …34 (76%) men; 44 probable AD, 1 definite) and 23 patients with DLB (mean age 71.6 years; 18 (78%) men; 6 possible DLB, 16 probable, 1 definite). The concentrations of all neurotransmitter metabolites, as well as those for t-tau and p-tau protein, were significantly lower in DLB compared to AD, irrespective of the diagnostic certainty (i.e., possible or probable). The currently used combination of Aβ42 , p-tau, and t-tau yielded a sensitivity of 92.9% and a specificity of 90%. The addition of MHPG resulted in an increased sensitivity of 97.6% and a specificity of 95% for the discrimination between DLB and AD. In conclusion, the combination of MHPG and the brain specific proteins t-tau, p-tau, and Aβ42 in CSF were associated with the clinical diagnosis of DLB and discriminated between AD and DLB with high diagnostic accuracy, suggesting this combination as a potential biomarker for DLB. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebrospinal fluid, dementia with Lewy bodies, diagnosis, MHPG, neurotransmitter metabolites, tau

DOI: 10.3233/JAD-2011-110482

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 377-384, 2011

Authors: Matsuda, Shuji | Tamayev, Robert | D'Adamio, Luciano

Article Type: Research Article

Abstract: An autosomal dominant mutation in the BRI2/ITM2B gene causes Familial Danish Dementia (FDD). We have generated a mouse model of FDD, called FDDKI , genetically congruous to the human disease. These mice carry one mutant and one wild type Bri2/Itm2b allele, like FDD patients. Analysis of FDDKI mice and samples from human patients has shown that the Danish mutation causes loss of Bri2 protein. FDDKI mice show synaptic plasticity and memory impairments. BRI2 is a physiological interactor of amyloid-β protein precursor (AβPP), a gene associated with Alzheimer's disease, which inhibits processing of AβPP. AβPP/Bri2 complexes are reduced in …synaptic membranes of FDDKI mice. Consequently, AβPP metabolites derived from processing of AβPP by β-, α-, and γ-secretases are increased in Danish dementia mice. AβPP haplodeficiency prevents memory and synaptic dysfunctions, consistent with a role for AβPP-metabolites in the pathogenesis of memory and synaptic deficits. This genetic suppression provides compelling evidence that AβPP and BRI2 functionally interact. Here, we have investigated whether AβPP processing is altered in FDD patients' brain samples. We find that the levels of several AβPP metabolites, including Aβ, are significantly increased in the brain sample derived from an FDD patient. Our data are consistent with the findings in FDDKI mice, and support the hypothesis that the neurological effects of the Danish form of BRI2 are caused by toxic AβPP metabolites, suggesting that Familial Danish and Alzheimer's dementias share common pathogenic mechanisms. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, BRI2, familial danish dementia

DOI: 10.3233/JAD-2011-110785

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 385-391, 2011

Authors: Jessen, Frank | Lewczuk, Piotr | Gür, Okan | Block, Wolfgang | Ende, Gabriele | Frölich, Lutz | Hammen, Thilo | Arlt, Sönke | Kornhuber, Johannes | Kucinski, Thomas | Popp, Julius | Peters, Oliver | Maier, Wolfgang | Träber, Frank | Wiltfang, Jens

Article Type: Research Article

Abstract: The interplay of amyloid and mitochondrial function is considered crucial in the pathophysiology of Alzheimer's disease (AD). We tested the association of the putative marker of mitochondrial function N-acetylaspartate (NAA) as measured by proton magnetic resonance spectroscopy within the medial temporal lobe and cerebrospinal fluid amyoid-β42 (Aβ42 ), total Tau and pTau181. 109 patients were recruited in a multicenter study (40 mild AD patients, 14 non-AD dementia patients, 29 mild cognitive impairment (MCI) AD-type patients, 26 MCI of non-AD type patients). NAA correlated with Aβ42 within the AD group. Since the NAA concentration is coupled to neuronal mitochondrial …function, the correlation between NAA and Aβ42 may reflect the interaction between disrupted mitochondrial pathways and amyloid production. Show more

Keywords: Alzheimer's disease, amyloid-β42, N-acetylaspartate, medial temporal lobe, mitochondria, proton MR spectrocopy

DOI: 10.3233/JAD-2011-110398

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 393-399, 2011

Authors: Du, Xue-ting | Wang, Li | Wang, Yu-jiong | Andreasen, Maria | Zhan, Da-wei | Feng, Ying | Li, Min | Zhao, Min | Otzen, Daniel | Xue, Di | Yang, Yang | Liu, Rui-tian

Article Type: Research Article

Abstract: Amyloid-β (Aβ40/42 ) aggregates containing the cross-β-sheet structure are associated with the pathogenesis of Alzheimer's disease (AD). It is generally accepted that the N-terminal peptide of Aβ40/42 , Aβ1-16 , does not aggregate, and is not cytotoxic. However, we here show that Aβ1-16 can aggregate, and form cytotoxic aggregates containing β-turns and regular non-amyloid β-sheet structures. Factors such as pH, ionic strength, and agitation were found to influence Aβ1-16 aggregation, and the amino acid residues Asp1, His6, Ser8, and Val12 in Aβ1-16 may play a role in this aggregation. Our MTT results showed that Aβ1-16 monomers …or oligomers were toxic to SH-SY5Y cells, but Aβ1-16 fibrils exhibited less cytotoxicity. Our studies also indicate that Aβ1-16 aggregates can increase the formation of reactive oxygen species and nitric oxide, induce the loss of calcium homeostasis, and incur the microglial production of TNF-α and IL-4. Thus, our findings suggest that Aβ1-16 may contribute to AD pathogenesis. Show more

Keywords: Aggregation, Alzheimer's disease, amyloid-β, neurotoxicity

DOI: 10.3233/JAD-2011-110476

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 401-413, 2011

Authors: Threlkeld, Zachary D. | Jicha, Greg A. | Smith, Charles D. | Gold, Brian T.

Article Type: Research Article

Abstract: Reduced task deactivation within regions of the default mode network (DMN) has been frequently reported in Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI). As task deactivation reductions become increasingly used in the study of early AD states, it is important to understand their relationship to atrophy. To address this issue, the present study compared task deactivation reductions during a lexical decision task and atrophy in aMCI, using a series of parallel voxel-wise and region-wise analyses of fMRI and structural data. Our results identified multiple regions within parietal cortex as convergence areas of task deactivation and atrophy in aMCI. …Relationships between parietal regions showing overlapping task deactivation reductions and atrophy in aMCI were then explored. Regression analyses demonstrated minimal correlation between task deactivation reductions and either local or global atrophy in aMCI. In addition, a logistic regression model which combined task deactivation reductions and atrophy in parietal DMN regions showed higher classificatory accuracy of aMCI than separate task deactivation or atrophy models. Results suggest that task deactivation reductions and atrophy in parietal regions provide complementary rather than redundant information in aMCI. Future longitudinal studies will be required to assess the utility of combining task deactivation reductions and atrophy in the detection of early AD. Show more

Keywords: Alzheimer's disease, atrophy, deactivation, default mode network (DMN), mild cognitive impairment, voxel-based morphometry

DOI: 10.3233/JAD-2011-110206

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 415-427, 2011

Authors: Oliveira, Sandra Marisa | Ribeiro, Carlos A. | Cardoso, Isabel | Saraiva, Maria João

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder affecting tens of millions of people worldwide, with women being at greater risk of developing the disease. A growing body of evidence suggests transthyretin (TTR) as an important modulator of AD pathogenesis. Aiming at providing further insight into the potential neuroprotective role of TTR and gender differences in AD, we crossed transgenic AβPPswe/PS1A246E mice with TTR-null mice and investigated both male and female AβPPswe/PS1A246E/TTR+/+ , AβPPswe/PS1A246E/TTR+/- , and AβPPswe/PS1A246E/TTR-/- animals for brain amyloid-β (Aβ) levels and deposition. The levels of circulating TTR between non-transgenic and AD mice were evaluated. Decreased levels of …circulating TTR in AD mice as compared to non-transgenic littermates were observed in early stages of AD-like neuropathology, but not at later stages where an opposite relationship was found. Elevated brain levels of Aβ42 were observed in AβPPswe/PS1A246E/TTR+/- female mice as compared to AβPPswe/PS1A246E/TTR+/+ female littermates; no significant differences were found among males of different TTR genotypes. We subsequently quantified the brain levels of testosterone and 17β-estradiol in these animals and verified that AβPPswe/PS1A246E/TTR+/- female mice present reduced brain levels of both hormones as compared to AβPPswe/PS1A246E/TTR+/+ females; no significant differences were detected among males of different TTR genotypes. Our results provide evidence for a gender-associated modulation of brain Aβ levels and brain sex steroid hormones by TTR, and suggest that reduced levels of brain testosterone and 17β-estradiol in female mice with TTR genetic reduction might underlie their increased AD-like neuropathology. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, 17β-estradiol, testosterone, transgenic mouse, transthyretin

DOI: 10.3233/JAD-2011-110488

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 429-439, 2011

Authors: Kim, Woojin S. | Hill, Andrew F. | Fitzgerald, Michael L. | Freeman, Mason W. | Evin, Genevieve | Garner, Brett

Article Type: Research Article

Abstract: Cerebral amyloid-β (Aβ) deposition is a critical feature of Alzheimer's disease. Aβ is derived from the amyloid-β protein precursor (AβPP) via two sequential cleavages that are mediated by β-secretase and the γ-secretase complex. Such amyloidogenic AβPP processing occurs in lipid raft microdomains of cell membranes and it is thought that modulating the distribution of lipids in rafts may regulate AβPP processing and Aβ production. Certain ATP-binding cassette (ABC) transporters regulate lipid transport across cell membranes and, as recent studies reveal, within membrane microdomains. ABCA1 also regulates Aβ metabolism in the brain although its direct impact on AβPP remains an open …question. Here we assessed the capacity of three ABCA1 mutants (that do not promote lipid efflux) to modulate AβPP processing. Unexpectedly, these non-functional mutants also reduced Aβ production similar to wild type ABCA1. ABCA1 expression did not alter AβPP localization in lipid rafts, and co-immunoprecipitation experiments indicated ABCA1 and AβPP physically interact. These data suggest that ABCA1 may regulate AβPP processing independent of its impact on membrane lipid homeostasis. Show more

Keywords: ABCA1, AβPP processing, Alzheimer's disease, lipid transport, membrane biology, Tangier disease

DOI: 10.3233/JAD-2011-110521

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 441-452, 2011

Authors: Grambaite, Ramune | Selnes, Per | Reinvang, Ivar | Aarsland, Dag | Hessen, Erik | Gjerstad, Leif | Fladby, Tormod

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) may affect multiple neuropsychological domains. While amnestic MCI is associated with Alzheimer's disease, patterns of brain pathology in non-amnestic subtypes have been less studied. Twenty-three patients with attention/executive MCI (a/e MCI), seen at a university-based memory clinic, and 23 normal controls, matched according to age, gender, and education, were included in this study. All subjects were assessed with a neuropsychological test battery, including tests of memory, attention and executive function, and underwent magnetic resonance imaging. Diffusion tensor imaging derived white matter (WM) tract radial and mean diffusivity (DR and MD) were assessed using Tract-Based Spatial Statistics, …and cortical thickness (CTH) was assessed using FreeSurfer. This study investigated changes of WM DR/MD and CTH in subjects with a/e MCI, and associations between these changes and different a/e subfunctions. WM DR/MD underlying rostral middle frontal, medial orbitofrontal, caudal anterior cingulate, posterior cingulate, retrosplenial and entorhinal cortices was higher for the a/e MCI than the control group, but CTH was not different from controls in any of the regions. WM DR/MD underlying superior frontal, rostral middle frontal, lateral/medial orbitofrontal and retrosplenial cortices were significantly associated with inhibition/switching performance, while caudal middle frontal CTH was significantly associated with attention and divided attention in the patient group. We conclude that increased WM DR/MD in frontal and cingulate regions and cortical thinning in caudal middle frontal region are both associated with executive dysfunction in MCI. Show more

Keywords: Alzheimer's disease, cortical thickness, diffusion tensor imaging, mild cognitive impairment, radial and mean diffusivity, white matter

DOI: 10.3233/JAD-2011-110290

Citation: Journal of Alzheimer's Disease, vol. 27, no. 2, pp. 453-462, 2011