Journal of Alzheimer's Disease - Volume 18, issue 2

Authors: Götz, Jürgen | Schonrock, Nicole | Vissel, Bryce | Ittner, Lars M.

Article Type: Review Article

Abstract: Neurodegenerative diseases are characterized by 'hot spots' of degeneration. The regions of primary vulnerability vary between different neurodegenerative diseases. Within these regions, some neurons are lost whereas others that are morphologically indiscriminate survive. The enigma of this selective vulnerability is tightly linked to two fundamental problems in the neurosciences. First, it is not understood how many neuronal cell types make up the mammalian brain; estimates are in the order of more than a thousand. Second, the mechanisms by which some nerve cells undergo functional impairment followed by degeneration while others do not, remain elusive. Understanding the basis for this selective …vulnerability has significant implications for understanding the pathogenesis of disease and for developing treatments. Here, we review what is known about selective vulnerability in Alzheimer's disease, frontotemporal dementia, and Parkinson's disease. We suggest, since transgenic animal models of disease reproduce aspects of selective vulnerability, that these models offer a valuable system for future investigations into the physiological basis of selective vulnerability. Show more

Keywords: Alzheimer's disease, amygdala, amyloid-β, frontotemporal dementia, hippocampus, neurofibrillary tangles, Parkinson's disease, tau

DOI: 10.3233/JAD-2009-1143

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 243-251, 2009

Authors: Taru, Hidenori | Suzuki, Toshiharu

Article Type: Review Article

Abstract: Amyloid-β protein precursor (AβPP) is a receptor-like, type-I membrane protein that plays a central role in the pathogenesis of Alzheimer's disease. The cytoplasmic domain of AβPP is important for the metabolism and physiological functions of AβPP and contains a GYENPTY motif that interacts with proteins that contain a phosphotyrosine binding (PTB) domain such as X11/Mint, FE65, and the JIP family of proteins. X11 and X11-like proteins are neuronal adaptor proteins involved in presynaptic function and the intracellular trafficking of proteins. Recent studies in X11s knockout mice confirmed findings from in vitro studies that X11 proteins affect AβPP metabolism and the …generation of amyloid-β peptide. FE65 proteins are involved in transactivation in coordination with the intracellular domain fragment of AβPP, and/or in cellular responses to DNA damage. Neurodevelopmental defects observed in FE65s double knockout mice suggest that FE65 proteins cooperate with AβPP to play a role in neuronal cytoskeletal regulation. c-Jun N-terminal kinase (JNK) interacting protein-1 (JIP-1), a scaffolding protein for the JNK kinase cascade, has been suggested to mediate the intracellular trafficking of AβPP by molecular motor kinesin-1. This article reviews some of the recent findings regarding the regulation of physiological function and metabolism of AβPP by AβPP binding proteins. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor (AβPP), binding, metabolism

DOI: 10.3233/JAD-2009-1148

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 253-265, 2009

Authors: Cammarata, Sergio | Borghi, Roberta | Giliberto, Luca | Pardini, Matteo | Pollero, Valeria | Novello, Cristina | Fornaro, Michele | Vitali, Antonella | Bracco, Laura | Caltagirone, Carlo | Bossù, Paola | Odetti, Patrizio | Tabaton, Massimo

Article Type: Short Communication

Abstract: Amnestic mild cognitive impairment (aMCI) is considered a prodromal stage of Alzheimer's disease (AD). We measured plasma levels of amyloid-β40 (Aβ40 ) and Aβ42 in 191 subjects with aMCI. Seventy-nine of them were clinically followed for two years. In the total cohort of aMCI cases, the average level of Aβ42 , as well as the Aβ42 /Aβ40 ratio, was significantly higher than those of the 102 cognitively normal age-matched subjects. The aMCI cases that converted to probable AD within 2 years had higher levels of Aβ42 and, to a lesser extent, Aβ40 than the stable …cases. However the large variability of measured values indicates that plasma Aβ is not a suitable marker of incipient AD. Show more

Keywords: Alzheimer's disease, amyloid-β, mild cognitive impairment, plasma

DOI: 10.3233/JAD-2009-1144

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 267-271, 2009

Authors: Mi, Weiqian | Jung, Sonia S. | Yu, Haung | Schmidt, Stephen D. | Nixon, Ralph A. | Mathews, Paul M. | Tagliavini, Fabrizio | Levy, Efrat

Article Type: Research Article

Abstract: A role for cystatin C (CysC) in the pathogenesis of Alzheimer's disease (AD) has been suggested by the genetic linkage of a CysC gene (CST3) polymorphism with late-onset AD, the co-localization of CysC with amyloid-β (Aβ) in AD brains, and binding of CysC to soluble Aβ in vitro and in mouse models of AD. This study investigates the binding between Aβ and CysC in the human central nervous system. While CysC binding to soluble Aβ was observed in AD patients and controls, a SDS-resistant CysC/Aβ complex was detected exclusively in brains of neuropathologically normal controls, but not in AD cases. …The association of CysC with Aβ in brain from control individuals and in cerebrospinal fluid reveals an interaction of these two polypeptides in their soluble form. The association between Aβ and CysC prevented Aβ accumulation and fibrillogenesis in experimental systems, arguing that CysC plays a protective role in the pathogenesis of AD in humans and explains why decreases in CysC concentration caused by the CST3 polymorphism or by specific presenilin 2 mutations can lead to the development of the disease. Thus, enhancing CysC expression or modulating CysC binding to Aβ have important disease-modifying effects, suggesting a novel therapeutic intervention for AD. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, cystatin C

DOI: 10.3233/JAD-2009-1147

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 273-280, 2009

Authors: Ramírez-Lugo, Leticia | Jensen, Morten S. | Søderman, Andreas | West, Mark J.

Article Type: Research Article

Abstract: Age-related changes in taste memory were evaluated in APPswe/PS1dE9 transgenic (Tg) mice and age-matched wild type littermate controls (Wt). These Tg mice produce increasing amounts of amyloid-β in the brain with age, develop significant amounts of plaques by 9 months of age, and provide an opportunity to study the effects of Alzheimer's disease-like amyloidosis on different aspects of taste memory. In groups of mice ranging from 15–16 months of age, the neophobic response and its attenuation were similar in Tg and Wt mice. However, conditioned taste aversion (CTA), which resulted from the association between a new taste and an artificially …induced gastric malaise, was significantly reduced in the 15–16 month old Tg mice compared to the Wt mice, but not in the 34 –or 7–8 month old mice. The extinction of CTA was normal in 34 –month old Tg mice, but occurred more rapidly in the 7–8 and 15–16 months old Tg mice than in the age-matched controls. These results provide evidence of differences in the neuronal systems involved in the attenuation of neophobia and CTA and suggest that the progressive amyloidosis that takes place in APPswe/PS1dE9 mice selectively affects the aversion component of taste memory. Show more

Keywords: Alzheimer's disease, conditioned taste aversion, learning, safe taste memory, transgenic mice

DOI: 10.3233/JAD-2009-1141

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 281-293, 2009

Authors: Ghidoni, Roberta | Albertini, Valentina | Squitti, Rosanna | Paterlini, Anna | Bruno, Anna | Bernardini, Silvia | Cassetta, Emanuele | Rossini, Paolo Maria | Squitieri, Ferdinando | Benussi, Luisa | Binetti, Giuliano

Article Type: Research Article

Abstract: A novel missense mutation (T719P) in the amyloid-β protein precursor (AβPP) gene was discovered in a 46-year old patient affected by early onset familial Alzheimer's disease. Using surface enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS), we determined mass profiles of amyloid-β peptides (Aβ) in cerebrospinal fluid (CSF) of the AβPP mutated patient, healthy control subjects (n = 10), and of two subjects carrying mutations in presenilins genes (PS) (i.e., PS1 P117L and PS2 T122R): seven different C-terminally and three N-terminally truncated Aβ peptides were found in CSF. The investigated AβPP as well as PS mutations were associated with an overall …reduction of Aβ species, except for Aβ10-40 . Interestingly, the AβPP T719P mutation unbalanced the relative proportion of Aβ peptides with a reduction of Aβ1-40 and Aβ1-42 paralleled by an increase of Aβ1-38 and Aβ10-40 . Despite the specific neuropeptidomic phenotype associated with the AβPP T719P mutation, the enrichment in Aβ10-40 paralleled by depletion of Aβ1-42 seems to be a common theme in familial AD. The AβPP T719P mutation is of particular interest because it is the only mutation located in close proximity to the AβPP ε-cleavage site. Show more

Keywords: Amyloid-β protein precursor (AβPP) transmembrane domain, cleavage site at Aβ48, ε-cleavage, familial Alzheimer's disease (FAD), γ-secretase, N- and C-terminally truncated amyloid-β peptides, presenilins, surface enhanced laser desorption/ionization mass spectrometry (SELDI-TOF MS)

DOI: 10.3233/JAD-2009-1142

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 295-303, 2009

Authors: Chen, Mengqi | Martins, Ralph N. | Lardelli, Michael

Article Type: Research Article

Abstract: Microtubule-associated protein tau (MAPT) is the major component of the neurofibrillary tangles found in the brains of those suffering from Alzheimer's disease. Various forms of tau lesions are found in other neurodegenerative diseases (tauopathies). We report identification of two MAPT paralogous genes in zebrafish, mapta and maptb, and analysis of their expression patterns during embryonic development. The two paralogues appear to have arisen by duplication of an ancestral teleost MAPT orthologue. Analysis of the splicing of transcripts from both genes during embryogenesis showed that mapta can be spliced into isoforms with between four and six tubulin-binding repeats (4R-6R), while maptb …is mainly spliced into 3R isoforms. Expression of both genes is observed predominantly in the developing central nervous system. A particularly large isoform of maptb is specifically expressed in the trigeminal ganglion and in dorsal sensory neurons of the spinal cord. Changes in the subcellular ratio of 3R and 4R isoforms can have pathological consequences in mammals. The predominant production of 4R-6R isoforms from mapta and of 3R isoforms from maptb suggests that zebrafish embryos will be a useful tool with which to study the discrete functions and interactions of the 3R and 4R MAPT isoforms. Show more

Keywords: Alzheimer's disease, Danio rerio, embryo, expression, isoform, MAPT, orthologue, tau, zebrafish

DOI: 10.3233/JAD-2009-1145

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 305-317, 2009

Authors: Jansen, Paula J. | Lütjohann, Dieter | Thelen, Karin M. | von Bergmann, Klaus | van Leuven, Fred | Ramaekers, Frans C.S. | Monique, Monique

Article Type: Research Article

Abstract: Apolipoprotein E (apoE) is a regulator of peripheral cholesterol homeostasis, and the apoE-isoform E4 is a major risk factor for the development of Alzheimer's disease (AD). Accumulating evidence suggests a key role for aberrant cholesterol metabolism in AD. We hypothesized that apoE-deficiency in mice not only affects cholesterol homeostasis in the periphery, but also in the brain, and that this can be restored by astrocyte-specific expression of human apoE3, but not apoE4. Using gas-chromatography mass-spectrometry, we found that absence of apoE in mice does not affect brain cholesterol homeostasis although serum sterol levels increase dramatically, especially when the apoE-knockout mice …are fed a high fat diet. We provide evidence suggesting that apoD and the ATP-binding Cassette Transporter A1 (ABCA1) play a compensatory role in the apoE-deficient brain. Surprisingly, astrocyte-specific expression of human apoE3 or apoE4 in brains of apoE-knockout mice significantly increases brain levels of cholesterol and its precursors compared to control mice, indicative of an increased cholesterol synthesis rate in the brain. This increase is independent of the apoE-isoform, suggesting that the detrimental effect of apoE4 on the pathogenesis of AD is unlikely to be due to an apoE-isoform effect on brain cholesterol homeostasis. Show more

Keywords: ABCA1, Alzheimer's disease, apolipoprotein D, apolipoprotein E, cholesterol metabolism, transgenic mice

DOI: 10.3233/JAD-2009-1150

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 319-329, 2009

Authors: Straten, Guido | Eschweiler, Gerhard W. | Maetzler, Walter | Laske, Christoph | Leyhe, Thomas

Article Type: Research Article

Abstract: As neurotrophic factors play an important role in development and maintenance of global central nervous system (CNS) function, we supposed that glial cell-line derived neurotrophic factor (GDNF), which has been extensively studied for its survival promoting effects especially concerning catecholaminergic neurons, also plays a significant role in neurodegenerative disease characterized mainly by damage of cholinergic CNS neurons like AD. Here we compared GDNF concentrations in serum and cerebrospinal fluid (CSF) of patients with probable Alzheimer's disease (AD) and normal controls (NC). While GDNF concentrations in CSF were significantly increased in patients with AD (291.7 ± 85.8 pg/ml) compared with NC …subjects (218.7 ± 93.3 pg/ml, p = 0.012), GDNF concentration of AD patients (486.5 ± 72.3 pg/ml) in serum were significantly decreased compared with the NC group (711.5 ± 186.5 pg/ml, p < 0.001). Increased GDNF in CSF of AD might be due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease and/or impairment of CSF turnover. Decreased serum concentration of GDNF might be related to altered function of the blood brain barrier thus disturbing clearance or facilitating passover of potentially harmful metabolites. Show more

Keywords: Alzheimer's disease, blood brain barrier, glial cell-line derived neurotrophic factor (GDNF), neuroprotection, neurotrophic effect

DOI: 10.3233/JAD-2009-1146

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 331-337, 2009

Authors: Lee, Myeong Soo | Yang, Eun Jin | Kim, Jong-In | Ernst, Edzard

Article Type: Research Article

Abstract: The objective of this review is to assess the clinical evidence for or against ginseng as a treatment for Alzheimer's disease (AD). We searched 20 databases from their inception to January 2009 and included all randomized clinical trials (RCTs) of any type of Panax ginseng to treat human patients suffering from AD. Methodological quality was assessed using the Jadad score. Two RCTs met all inclusion criteria. They assessed the effectiveness of ginseng as an adjunct to drug therapy on cognitive function compared with conventional drug therapy. Their results suggested significant effect in favor of ginseng on the Mini-Mental Status Examination …(n = 174, weight mean difference (WMD), 1.85; 95% confidence intervals, CIs 0.88 to 2.82, P = 0.0002) and on the Alzheimer's Disease Assessment Scale (ADAS)-cognitive (n = 174, WMD, 3.09; 95% CIs 1.08 to 5.09, P = 0.003). Both of these studies are burdened with serious methodological limitations. In conclusion, the evidence for ginseng as a treatment of AD is scarce and inconclusive. Further rigorous trials seem warranted. Show more

Keywords: Alzheimer's disease, cognitive function, Panax ginseng, systematic review

DOI: 10.3233/JAD-2009-1149

Citation: Journal of Alzheimer's Disease, vol. 18, no. 2, pp. 339-344, 2009