Journal of Alzheimer's Disease - Volume 22, issue 2

Authors: Timmer, Nienke M. | Kuiperij, H. Bea | de Waal, Robert M.W. | Verbeek, Marcel M.

Article Type: Review Article

Abstract: Senile plaques and cerebral amyloid angiopathy in Alzheimer's disease (AD) patients not only consist of the amyloid-β protein (Aβ), but also contain many different Aβ-associated factors, such as heparan sulfate proteoglycans, apolipoproteins, and complement factors. These factors may all influence Aβ deposition, aggregation, and clearance and therefore seem important in the development of human Aβ deposits. To study AD pathology and test new therapeutic agents, many different mouse models have been created. By transgenic expression of the amyloid-β protein precursor, frequently in combination with other transgenes, these animals develop Aβ deposits that morphologically resemble their human counterparts. Whether this resemblance …also applies to the presence of Aβ-associated factors is largely unclear. In this review, the co-deposition of factors known to associate with human Aβ deposits is summarized for several different AD mouse models. Show more

Keywords: Acute-phase proteins, Alzheimer's disease, amyloid-β, apolipoprotein E, complement, heparan sulfate proteoglycans, transgenic mice

DOI: 10.3233/JAD-2010-100711

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 345-355, 2010

Authors: Mutter, Joachim | Curth, Annika | Naumann, Johannes | Deth, Richard | Walach, Harald

Article Type: Review Article

Abstract: Mercury is one of the most toxic substances known to humans. It has been introduced into the human environment and has also been widely used in medicine. Since circumstantial evidence exists that the pathology of Alzheimer's disease (AD) might be in part caused or exacerbated by inorganic mercury, we conducted a systematic review using a comprehensive search strategy. Studies were screened according to a pre-defined protocol. Two reviewers extracted relevant data independent of each other. One thousand and forty one references were scrutinized, and 106 studies fulfilled the inclusion criteria. Most studies were case control or comparative cohort studies. Thirty-two …studies, out of 40 testing memory in individuals exposed to inorganic mercury, found significant memory deficits. Some autopsy studies found increased mercury levels in brain tissues of AD patients. Measurements of mercury levels in blood, urine, hair, nails, and cerebrospinal fluid were inconsistent. In vitro models showed that inorganic mercury reproduces all pathological changes seen in AD, and in animal models inorganic mercury produced changes that are similar to those seen in AD. Its high affinity for selenium and selenoproteins suggests that inorganic mercurymay promote neurodegenerative disorders via disruption of redox regulation. Inorganic mercury may play a role as a co-factor in the development of AD. It may also increase the pathological influence of other metals. Our mechanistic model describes potential causal pathways. As the single most effective public health primary preventive measure, industrial, and medical usage of mercury should be eliminated as soon as possible. Show more

Keywords: Alzheimer's disease, inorganic mercury, neurotoxicity, selenium, systematic review

DOI: 10.3233/JAD-2010-100705

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 357-374, 2010

Authors: Jiménez, Juan S.

Article Type: Review Article

Abstract: A number of neurodegenerative diseases, including Alzheimer's disease, tauopathies, Parkinson's disease, and synucleinopathies, polyglutamine diseases, including Huntington's disease, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathy, are characterized by the existence of a protein or peptide prone to aggregation specific to the disease: amyloid-β, tau protein, α-synuclein, atrophin 1, androgen receptor, prion protein, copper-zinc superoxide dismutase, α 1A subunit of CaV2.1, TATA-box binding protein, huntingtin, and ataxins 1, 2, 3, and 7. Beside this common molecular feature, we have found three additional main properties related to the disease-connected protein or peptide, which are shared by all those neurological disorders: first, proneness …to aggregation, which, in many cases, seems to be bound to the lack of a clearly defined secondary structure; second, reported presence of the disease-related protein inside the nucleus; and finally, an apparently unspecific interaction with DNA. These findings, together with the lack of clear details to explain the molecular origin of these neurodegenerative diseases, invite a hypothesis that, together with other plausible molecular explanations, may contribute to find the molecular basis of these diseases: I propose here the hypothesis that many neurological disorders may be the consequence, at least in part, of an aberrant interaction of the disease-related protein with nucleic acids, therefore affecting the normal DNA expression and giving place to a genetic stress which, in turn, alters the expression of proteins needed for the normal cellular function and regulation. Show more

Keywords: Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, polyglutamine diseases, transmissible spongiform encephalopathy

DOI: 10.3233/JAD-2010-100189

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 375-391, 2010

Authors: Struble, Robert G. | Ala, Tom | Patrylo, Peter R. | Brewer, Gregory J. | Yan, Xiao-Xin

Article Type: Review Article

Abstract: The amyloid cascade hypothesis has guided much of the research into Alzheimer's disease (AD) over the last 25 years. We argue that the hypothesis of amyloid-β (Aβ) as the primary cause of dementia may not be fully correct. Rather, we propose that decline in brain metabolic activity, which is tightly linked to synaptic activity, actually underlies both the cognitive decline in AD and the deposition of Aβ. Aβ may further exacerbate metabolic decline and result in a downward spiral of cognitive function, leading to dementia. This novel interpretation can tie the disparate risk factors for dementia to a unifying hypothesis …and present a roadmap for interventions to decrease the prevalence of dementia in the elderly population. Show more

Keywords: Amyloid-β protein, apolipoprotein E, dementia, etiology, metabolism, mitochondria, pathology, olfactory pathways, therapeutics

DOI: 10.3233/JAD-2010-100846

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 393-399, 2010

Authors: Ross, Joel S. | Imbimbo, Bruno P.

Article Type: Short Communication

Abstract: The recent failure of semagacestat in two large Phase III studies questions the value of γ-secretase inhibitors in treating Alzheimer's disease. Understanding the reasons of this setback may be important for the future research on effective treatments for this devastating disease.

DOI: 10.3233/JAD-2010-101548

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 401-404, 2010

Authors: Gil-Bea, Francisco J. | Solas, Maite | Solomon, Alina | Mugueta, Carmen | Winblad, Bengt | Kivipelto, Miia | Ramirez, Maria J. | Cedazo-Mínguez, Angel

Article Type: Research Article

Abstract: Previous studies have failed to reach consensus on insulin levels in cerebrospinal fluid of Alzheimer's disease (AD) patients and on its relation to pathological features. We performed a new analysis in patients at different stages of AD, and investigated the relationship of insulin levels with biochemical disease markers and with cognitive score. We included 99 patients from our Memory Clinic (Karolinska University Hospital, Sweden), including: 27 patients with mild AD, 13 that progressed from mild cognitive impairment (MCI) to AD in two years time, 26 with MCI stable after two years, and 33 with subjective cognitive impairment. Insulin was significantly …decreased in the cerebrospinal fluid of both women and men with mild AD. Insulin deficits were seen in women belonging to both MCI groups, suggesting that this occurs earlier than in men. Insulin was positively associated with amyloid-β 1–42 (Aβ1–42 ) levels and cognitive score. Furthermore, total-tau/(Aβ1–42 *insulin) ratio showed strikingly better sensitivity and specificity than the total-tau/Aβ1–42 ratio for early AD diagnosis in women. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, insulin, mild cognitive impairment, women

DOI: 10.3233/JAD-2010-100795

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 405-413, 2010

Authors: Rosengarten, Bernhard | Dannhardt, Veren | Burr, Ole | Pöhler, Matthias | Rosengarten, Susanne | Oechsner, Matthias | Reuter, Iris

Article Type: Research Article

Abstract: Alzheimer's disease (AD) and Parkinson's disease (PD) lead to a cholinergic deficit in the brain which is not only related to dementia, but may also lead to a disturbed neurovascular coupling. We investigated the effect of cholinergic decline on neurovascular coupling in PD patients. Patients with idiopathic PD were divided in groups without (n = 59; 65 ± 9 y) or with moderate dementia as specified by Mini-Mental State Examination. The demented patients were assigned to groups with (n = 55; 73 ± 6 y) or without (n = 61; 72 ± 8 y) acetylcholinesterase inhibitor treatment. Neurovascular coupling was …assessed by a simultaneous electroencephalography-Doppler technique applying a contrast-based visual stimulation task. Visually evoked potential amplitudes (N75-P100) and parameters of the hemodynamic response in the posterior cerebral artery were obtained using a control system approach (resting flow velocity, gain, attenuation, rate time, and natural frequency). Data were compared to a healthy control group of a similar age range (n = 20; 63 ± 8 yr). Compared to controls, patient groups presented no differences in evoked potential amplitudes or neurovascular coupling parameters. The reported 30% decline in acetylcholinesterase activity in PD patients did not lead to measurable changes in neurovascular coupling. In AD patients additional factors might explain the uncoupling and higher cerebrovascular risk detected in clinical studies. Show more

Keywords: Alzheimer's disease, cerebral blood flow, dementia, functional activation, neurovascular coupling, Parkinson's disease, visually evoked potential

DOI: 10.3233/JAD-2010-101140

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 415-421, 2010

Authors: Kapoor, Arun | Hsu, Wen-Ming | Wang, Bo-Jeng | Wu, Guan-Hsun | Lin, Ti-Yu | Lee, Shyh-Jye | Yen, Chen-Tung | Liang, Shu-Mei | Liao, Yung-Feng

Article Type: Research Article

Abstract: Amyloidogenic processing of amyloid-β precursor protein (AβPP) is associated with cholesterol- and sphingolipid-rich lipid rafts. Caveolin-1, a raft-residing protein, has been implicated in the pathogenesis of Alzheimer's disease. To determine the role of caveolin-1 in governing γ-secretase-mediated AβPP proteolysis, cellular γ-secretase activity was assessed in response to alteration in caveolin-1 expression. We demonstrated that suppression of caveolin-1 expression by RNA interference resulted in a significant increase in γ-secretase-mediated proteolysis of AβPP, generation of amyloid-β, and cleavage of Notch. Overexpression of caveolin-1 attenuated γ-secretase-mediated proteolysis of AβPP and Notch, substantiating the negative regulation of γ-secretase by caveolin-1. Furthermore, we found that …cells deficient in caveolin-1 exhibited significantly increased co-localization of γ-secretase with clathrin-coated non-caveolar endocytic vesicles, demonstrating that the partitioning of γ-secretase between caveolar and non-caveolar membranes can be modulated by caveolin-1. Our data also showed that JNK activation is essential for caveolin-1-mediated regulation of γ-secretase. Together, our results strongly suggest that caveolin-1 is an important regulator of γ-secretase activity. Show more

Keywords: Amyloid-β, amyloid-β precursor protein, caveolin-1, clathrin, γ-secretase, lipid raft

DOI: 10.3233/JAD-2010-100531

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 423-442, 2010

Authors: Liu, Dong | Pitta, Michael | Lee, Jong-Hwan | Ray, Balmiki | Lahiri, Debomoy K. | Furukawa, Katsutoshi | Mughal, Mohamed | Jiang, Haiyang | Villarreal, Julissa | Cutler, Roy G. | Greig, Nigel H. | Mattson, Mark P.

Article Type: Research Article

Abstract: Compromised cellular energy metabolism, cerebral hypoperfusion, and neuronal calcium dysregulation are involved in the pathological process of Alzheimer's disease (AD). ATP-sensitive potassium (KATP ) channels in plasma membrane and inner mitochondrial membrane play important roles in modulating neuronal excitability, cell survival, and cerebral vascular tone. To investigate the therapeutic potential of drugs that activate KATP channels in AD, we first characterized the effects of the KATP channel opener diazoxide on cultured neurons, and then determined its ability to modify the disease process in the 3xTgAD mouse model of AD. Plasma and mitochondrial membrane potentials, cell excitability, intracellular Ca2+ …levels and bioenergetics were measured in cultured cerebral cortical neurons exposed to diazoxide. Diazoxide hyperpolarized neurons, reduced the frequency of action potentials, attenuated Ca2+ influx through NMDA receptor channels, and reduced oxidative stress. 3xTgAD mice treated with diazoxide for 8 months exhibited improved performance in a learning and memory test, reduced levels of anxiety, decreased accumulation of Aβ oligomers and hyperphosphorylated tau in the cortex and hippocampus, and increased cerebral blood flow. Our findings show that diazoxide can ameliorate molecular, cytopathological, and behavioral alterations in a mouse model of AD suggesting a therapeutic potential for drugs that activate KATP channels in the treatment of AD. Show more

Keywords: 3xTgAD, calcium, cerebral blood flow, diazoxide, excitotoxicity, hippocampus, hyperpolerization, learning and memory, K ATP channels

DOI: 10.3233/JAD-2010-101017

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 443-457, 2010

Authors: Popp, Julius | Lewczuk, Piotr | Frommann, Ingo | Kölsch, Heike | Kornhuber, Johannes | Maier, Wolfgang | Jessen, Frank

Article Type: Research Article

Abstract: In Alzheimer's disease (AD), the cerebral pathological changes begin many years before the clinical manifestation of the disease. Biomarkers for AD, such as the cerebrospinal fluid (CSF) concentrations of amyloid-β1–42 (Aβ1–42 ) and tau phosphorylated at threonine 181 (pTau181), may reflect these cerebral changes relatively early. Accordingly, cognitively healthy subjects at risk for AD often have altered CSF concentrations of Aβ1–42 and pTau181. In this study, we assessed the effects and interaction of two strong risk factors for AD, aging and the presence of the APOEε4 allele, on the CSF Aβ1–42 and pTau181 concentrations in 280 adults …with normal cognition across the lifespan. For comparison, we further included 152 patients with probable AD. We found significant effects of age on the CSF Aβ1–42 and pTau181, and of the APOEε4 genotype on the Aβ1–42 levels in the cognitively normal participants. Carrying the APOEε4 allele was associated with a significant decrease of the Aβ1–42 concentrations in middle-aged and older participants. In the group of participants with AD, the Aβ1–42 levels were significantly lower in the APOEε4 carriers compared to the non-carriers. These findings demonstrate significant age effects on the CSF Aβ1–42 and pTau181 across lifespan. They also suggest that the decrease of Aβ1–42 , but not the increase of pTau181 CSF levels is accelerated by the APOEε4 genotype in middle-aged and older adults with normal cognition. Show more

Keywords: Alzheimer's disease, amyloid-β, APOEε4, cerebrospinal fluid, hyperphosphorylated tau, normal aging

DOI: 10.3233/JAD-2010-100561

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 459-468, 2010

Authors: Arbel-Ornath, Michal | Becker, Maria | Rabinovich-Toidman, Polina | Gartner, Myra | Solomon, Beka

Article Type: Research Article

Abstract: Among the different paradigms aimed at interfering with amyloid-β (Aβ)-related pathology, the attenuation of amyloid-β protein precursor (AβPP) processing to limit Aβ levels seems to be a promising one. Along with the development of BACE1 inhibitors, and the generation of its knock-out mice, accumulating data raise concerns regarding a total inhibition of the enzyme as it shares the processing of other substrates. We described a novel approach to interfere with the specific interaction between AβPP and BACE1 using monoclonal antibodies directed to the β-secretase cleavage site upon the substrate, AβPP. Such antibodies limit AβPP cleavage in a cellular model of …Alzheimer's disease (AD) and avoid the total inhibition of BACE1. Here, we demonstrate the ability of AβPP β-site antibodies to interfere with Aβ production in vivo. Systemic antibody treatment diminished Aβ plaques, membrane-associated oligomers, and intracellular Aβ accumulation, all of which have been implicated in cellular death and synaptic loss, suggesting that this approach may be an applicable strategy for AD treatment. Show more

Keywords: Alzheimer's disease, amyloid-β, AβPP β-site, β-secretase, immunotherapy, intracellular Aβ, monoclonal antibodies

DOI: 10.3233/JAD-2010-100753

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 469-482, 2010

Authors: Gu, Yian | Luchsinger, Jose A. | Stern, Yaakov | Scarmeas, Nikolaos

Article Type: Research Article

Abstract: We aimed to investigate the association between adherence to the Mediterranean diet (MeDi) and Alzheimer's disease (AD) risk in a prospective study. Specifically, we analyzed reduced inflammation and improved metabolic profile as a potential medium through which the MeDi reduced the risk of AD. During a 4-year follow-up, 118 incident AD cases were identified among the 1219 non-demented elderly (age ⩾ 65) subjects who provided dietary information and blood samples at baseline. We used high-sensitivity C-reactive protein (hsCRP) as an index of systemic inflammation, and fasting insulin and adiponectin as indexes of metabolic profile. We investigated whether there was a …change in the association between MeDi and incident AD risk when the biomarkers were introduced into multivariable adjusted COX models. Better adherence to MeDi was associated with lower level of hsCRP (p = 0.003), but not fasting insulin or adiponectin. Better adherence to MeDi was significantly associated with lower risk for AD: compared to those in the lowest tertile of MeDi, subjects in the highest tertile had a 34% less risk of developing AD (p-for-trend = 0.04). Introduction of the hsCRP, fasting insulin, adiponectin, or combinations of them into the COX model did not change the magnitude of the association between MeDi and incident AD. Ultimately, the favorable association between better adherence to MeDi and lower risk of AD did not seem to be mediated by hsCRP, fasting insulin, or adiponectin. Other aspects of inflammatory and metabolic pathways not captured by these biomarkers, or non-inflammatory or non-metabolic pathways, may be relevant to the MeDi-AD association. Show more

Keywords: Adiponectin, Alzheimer's disease, C-reactive protein, cohort studies, epidemiology, insulin, Mediterranean diet

DOI: 10.3233/JAD-2010-100897

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 483-492, 2010

Authors: Blanco, Almudena | Álvarez, Susana | Fresno, Manuel | Muñoz-Fernández, Maria Ángeles

Article Type: Research Article

Abstract: Both amyloid-β peptide 1–42 (Aβ1–42 ) formation and cyclooxygenase-2 (COX-2) have been involved in the pathogenesis of Alzheimer's disease (AD), a devastating neurological disorder. However, the relationship between Aβ1–42 and COX-2 is unclear. We found that the addition of Aβ1–42 to astrocytoma cultures induced COX-2 mRNA and protein and PGE2 synthesis in primary human astrocytes and in human astrocytoma cell lines. Moreover, Aβ1–42 induced COX-2 promoter transcription. Deletion of nuclear factor-κB (NF-κB) sites of the promoter diminished Aβ1–42 -COX-2 dependent transcription. In agreement with this, Aβ1–42 induced transcription of NF-κB reporter gene. In contrast, Aβ1–42 …neither did not induce NFAT not AP-1 factors activation suggesting that both NFAT and AP-1 was not necessary to control COX-2 transcription induced by Aβ1–42 . Over expression of NF-κB inhibitory subunit, IκB, completely abrogated Aβ1–42 -induced COX-2 activity in U-87 cells, whereas the opposite effect was shown when p65/rel A NF-κB was over expressed. In addition, Aβ1–42 induced p65/rel A subunit translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NF-κB in COX-2 induction and PGE2 synthesis by Aβ1–42 was corroborated by using the pharmacological inhibitor of the NF-κB pathway, PDTC. In addition, Aβ1–42 treated astrocytoma supernatants were toxic for neuroblastoma cells, an effect which was blocked by PDTC. Summing up, our results indicate that Aβ1–42 was able to induce COX-2 and PGE2 synthesis in astrocytic cells through a NF-κB dependent mechanism. This may have implicated in our understanding of AD pathology. Show more

Keywords: Alzheimer's disease, amyloid-β1–42, astrocytes, COX-2, NF-κB, PGE2

DOI: 10.3233/JAD-2010-100309

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 493-505, 2010

Authors: Teipel, Stefan J. | Meindl, Thomas | Wagner, Maximilian | Stieltjes, Bram | Reuter, Sigrid | Hauenstein, Karl-Heinz | Filippi, Massimo | Ernemann, Ulrike | Reiser, Maximilian F. | Hampel, Harald

Article Type: Research Article

Abstract: Cross-sectional studies using diffusion tensor imaging (DTI) suggest decline of the integrity of intracortically projecting fiber tracts with aging and in neurodegenerative diseases, such as Alzheimer's disease (AD). Longitudinal studies on the change of fiber tract integrity in normal and pathological aging are still rare. Here, we prospectively studied 11 healthy elderly subjects and 14 subjects with amnestic mild cognitive impairment (MCI), a clinical risk group for AD, using high-resolution DTI and MRI at baseline and after 13 to 16 months follow-up. Fractional anisotropy (FA), a DTI measure of fiber tract integrity, was compared across time points and groups using …a repeated measures linear model and tract based spatial statistics. Additionally, we determined rates of grey matter and white matter atrophy using automated deformation based morphometry. Healthy elderly subjects showed decline of FA in intracortical projecting fiber tracts, such as corpus callosum, superior longitudinal fasciculus, uncinate fasciculus, inferior fronto-occipital fasciculus, and cingulate bundle (p < 0.05, corrected for multiple comparisons). MCI subjects showed significant FA decline predominantly in the anterior corpus callosum (p < 0.05, corrected for multiple comparisons). Grey and white matter atrophy involved prefrontal, parietal, and temporal lobe areas in controls and prefrontal, cingulate, and parietal lobe areas in MCI subjects and agreed with the pattern of fiber tract changes. Our findings indicate that DTI allows detection of microstructural changes in subcortical fiber tracts over time that are related to aging as well as to early stages of AD type neurodegeneration. The underlying mechanisms for these changes are unknown. Show more

Keywords: Cortical connectivity, fractional anisotropy, longitudinal study

DOI: 10.3233/JAD-2010-100234

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 507-522, 2010

Authors: Sala-Llonch, Roser | Bosch, Beatriz | Arenaza-Urquijo, Eider M. | Rami, Lorena | Bargalló, Núria | Junqué, Carme | Molinuevo, José-Luis | Bartrés-Faz, David

Article Type: Research Article

Abstract: We conducted an integrated multi-modal magnetic resonance imaging (MRI) study based on functional MRI (fMRI) data during a complex but cognitively preserved visual task in 15 amnestic mild cognitive impairment (a-MCI) patients and 15 Healthy Elders (HE). Independent Component Analysis of fMRI data identified a functional network containing an Activation Task Related Pattern (ATRP), including regions of the dorsal and ventral visual stream, and a Deactivation Task Related Pattern network (DTRP), with high spatial correspondence with the default-mode network (DMN). Gray matter (GM) volumes of the underlying ATRP and DTRP cortical areas were measured, and probabilistic tractography (based on diffusion …MRI) identified fiber pathways within each functional network. For the ATRP network, a-MCI patients exhibited increased fMRI responses in inferior-ventral visual areas, possibly reflecting compensatory activations for more compromised dorsal regions. However, no significant GM or white matter group differences were observed within the ATRP network. For the DTRP/DMN, a-MCI showed deactivation deficits and reduced GM volumes in the posterior cingulate/precuneus, excessive deactivations in the inferior parietal lobe, and less fiber tract integrity in the cingulate bundles. Task performance correlated with DTRP-functionality in the HE group. Besides allowing the identification of functional reorganizations in the cortical network directly processing the task-stimuli, these findings highlight the importance of conducting integrated multi-modal MRI studies in MCI based on spared cognitive domains in order to identify functional abnormalities in critical areas of the DMN and their precise anatomical substrates. These latter findings may reflect early neuroimaging biomarkers in dementia. Show more

Keywords: Alzheimer's disease, compensation, default-mode network, diffusion MRI, fMRI, mild cognitive impairment, structural magnetic resonance, tractography, visual pathways

DOI: 10.3233/JAD-2010-101038

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 523-539, 2010

Authors: Liu, Jinping | Chang, Lirong | Roselli, Francesco | Almeida, Osborne F.X. | Gao, Xiulai | Wang, Xiaomin | Yew, David T. | Wu, Yan

Article Type: Research Article

Abstract: Soluble oligomeric amyloid-β (Aβ) is thought to induce synaptic dysfunction during early stages of Alzheimer's disease (AD). In this report, we show that soluble Aβ downregulates the levels of two synaptic proteins, PSD-95 and synaptophysin, and that this effect can be blocked by MK-801 (NMDAR antagonist) and ifenprodil (NR2B antagonist). Low (1 μM) and high (10 μM) doses of NMDA, respectively, prevented and potentiated the actions of Aβ. Blockade of NR2A or synaptic NMDAR eliminated the protective effect of 1 μM NMDA, while the effects of 10 μM NMDA were only abolished by ifenprodil. Caspase-8, acting upstream of caspase-3, was …found to mediate the synaptotoxic actions of Aβ in an ifenprodil-reversible fashion. Thus, Aβ leads to a loss of synaptic proteins by suppression of NR2A function and activation of NR2B function and subsequent induction of caspase-8 and caspase-3 activities. The identified novel mechanism through which Aβ initiates synaptic dysfunction suggests that selective enhancement of NR2A activity and/or reduction of NR2B activity can halt the manifestation of a key early-stage event in AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, caspase, hippocampus, NMDA receptor

DOI: 10.3233/JAD-2010-100948

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 541-556, 2010

Authors: Viana, Ricardo J.S. | Ramalho, Rita M. | Nunes, Ana F. | Steer, Clifford J. | Rodrigues, Cecília M.P.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide- induced neurotoxicity is typically associated with apoptosis. In previous studies, we have shown that tauroursodeoxycholic acid (TUDCA), an endogenous anti-apoptotic bile acid, modulates Aβ-induced apoptosis. Here, we investigated stress signaling events triggered by soluble Aβ and further explored alternative pathways of neuroprotection by TUDCA in differentiated rat neuronal-like PC12 cells. Morphologic evaluation of apoptosis confirmed that Aβ-induced nuclear fragmentation was prevented by TUDCA. In addition, Aβ exposure resulted in activation of the early stress c-Jun N-terminal kinase (JNK) pathway, JNK nuclear translocation, and caspase-2 activation. Knock-down experiments of JNK established caspase-2 as a specific downstream target of …JNK in Aβ-induced apoptosis. Furthermore, active caspase-2 cleaved golgin-160 and was localized to the Golgi complex. Importantly, TUDCA abrogated Aβ-induced JNK/caspase-2 signaling. In conclusion, we show that JNK is the proximal stress sensor for soluble Aβ-induced toxicity, which translocates to the nucleus, activates caspase-2, and is strongly modulated by TUDCA in PC12 neuronal cells. Active caspase-2 cleaves golgin-160, suggesting caspase-2-dependent transduction of Aβ apoptotic signaling through the Golgi complex. These data provide new information linking apoptotic properties of Aβ peptide to distinct subcellular mechanisms of toxicity. Further characterization of this signaling pathway and exact targets of modulation are likely to provide new perspectives for modulation of amyloid-induced apoptosis by TUDCA. Show more

Keywords: Amyloid-β, apoptosis, c-Jun N-terminal kinase, caspase-2, Golgi complex, tauroursodeoxycholic acid

DOI: 10.3233/JAD-2010-100909

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 557-568, 2010

Authors: Baker, Laura D. | Frank, Laura L. | Foster-Schubert, Karen | Green, Pattie S | Wilkinson, Charles W. | McTiernan, Anne | Cholerton, Brenna A. | Plymate, Stephen R. | Fishel, Mark A. | Watson, G. Stennis | Duncan, Glen E. | Mehta, Pankaj D. | Craft, Suzanne

Article Type: Research Article

Abstract: Impaired glucose regulation is a defining characteristic of type 2 diabetes mellitus (T2DM) pathology and has been linked to increased risk of cognitive impairment and dementia. Although the benefits of aerobic exercise for physical health are well-documented, exercise effects on cognition have not been examined for older adults with poor glucose regulation associated with prediabetes and early T2DM. Using a randomized controlled design, twenty-eight adults (57–83 y old) meeting 2-h tolerance test criteria for glucose intolerance completed 6 months of aerobic exercise or stretching, which served as the control. The primary cognitive outcomes included measures of executive function (Trails B, …Task Switching, Stroop, Self-ordered Pointing Test, and Verbal Fluency). Other outcomes included memory performance (Story Recall, List Learning), measures of cardiorespiratory fitness obtained via maximal-graded exercise treadmill test, glucose disposal during hyperinsulinemic-euglycemic clamp, body fat, and fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulin-like growth factor-1, amyloid-β (Aβ40 and Aβ42 ). Six months of aerobic exercise improved executive function (MANCOVA, p = 0.04), cardiorespiratory fitness (MANOVA, p = 0.03), and insulin sensitivity (p = 0.05). Across all subjects, 6-month changes in cardiorespiratory fitness and insulin sensitivity were positively correlated (p = 0.01). For Aβ42 , plasma levels tended to decrease for the aerobic group relative to controls (p = 0.07). The results of our study using rigorous controlled methodology suggest a cognition-enhancing effect of aerobic exercise for older glucose intolerant adults. Although replication in a larger sample is needed, our findings potentially have important therapeutic implications for a growing number of adults at increased risk of cognitive decline. Show more

Keywords: Aerobic exercise, Alzheimer's disease, cognition, dementia, diabetes, executive function, glucose intolerance, prediabetes

DOI: 10.3233/JAD-2010-100768

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 569-579, 2010

Authors: Förster, Stefan | Vaitl, Andreas | Teipel, Stefan J. | Yakushev, Igor | Mustafa, Mona | la Fougère, Christian | Rominger, Axel | Cumming, Paul | Bartenstein, Peter | Hampel, Harald | Hummel, Thomas | Buerger, Katharina | Hundt, Walter | Steinbach, Silke

Article Type: Research Article

Abstract: We used [18 F]fluorodeoxyglucose (FDG) PET analysis to determine performance in different olfactory domains of patients with early AD compared to cognitively healthy subjects, and to map the functional metabolic representation of olfactory impairment in the patient sample. A cohort of patients with early AD (n = 24), consisting of 6 subjects with incipient AD and 18 subjects with mild AD, and a control group of 28 age-matched non-demented individuals were assembled. Patients and controls were tested for olfactory performance using the “Sniffin' Sticks” test battery [odor identification (ID), discrimination (DIS) and threshold (THR)], while patients additionally underwent resting state …FDG-PET. Voxel-wise PET results in the patients were correlated with olfaction scores using the general linear model in SPM5. Patients with early AD showed significantly reduced function in all three olfactory subdomains compared to controls. After controlling for effects due to patients' age, gender, cognitive status, and treating scores in the two other olfactory subdomains as nuisance variables, ID scores correlated with normalized FDG uptake in clusters with peaks in the right superior parietal lobule, fusiform gyrus, inferior frontal gyrus, and precuneus, while DIS scores correlated with a single cluster in the left postcentral cortex, and THR scores correlated with clusters in the right thalamus and cerebellum. The subtests employed in the “Sniffin' Sticks” test battery are complementary indicators of different aspects of olfactory dysfunction in early AD, and support the theory of a parallel organized olfactory system, revealed by FDG-PET correlation analysis. Show more

Keywords: Alzheimer's disease, FDG PET, mild cognitive impairment, olfactory system, smell test

DOI: 10.3233/JAD-2010-091549

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 581-591, 2010

Authors: Ellis, Grace | Fang, Erica | Maheshwari, Mukesh | Roltsch, Emily | Holcomb, Leigh | Zimmer, Danna | Martinez, Daniel | Murray, Ian V.J.

Article Type: Research Article

Abstract: Oxidative damage and amyloid-β (Aβ) protein misfolding are prominent features of Alzheimer's disease (AD). In vitro studies indicated a direct linkage between these two features, where lipid oxidation products augmented Aβ misfolding. We tested this linkage further, mimicking specific conditions present in amyloid plaques. In vitro lipid oxidation and lipid modification of Aβ were thus performed with elevated levels of copper or physiological levels of calcium. These in vitro experiments were then confirmed by in vivo immunohistochemical and chemical tagging of oxidative damage in brains from the PSAPP mouse model of AD. Our in vitro findings indicate that: 1) high …levels of copper prevent lipid oxidation; 2) physiological concentrations of calcium reduce 4 hydroxy-2-nonenal (HNE) modification of Aβ; and 3) anti-Aβ and HNE antibody epitopes are differentially masked. In vivo we demonstrated increased lipid oxidation around plaques but 4) a lack of immunological colocalization of HNE-adducts with Aβ. Thus, the lack of colocalization of Aβ and HNE-adduct immunostaining is most likely due to a combination of metals inhibiting HNE modification of Aβ, quenching lipid oxidation and a masking of HNE-Aβ histopathology. However, other forms of oxidative damage colocalize with Aβ in plaques, as demonstrated using a chemical method for identifying oxidative damage. Additionally, these findings suggest that HNE modification of Aβ may affect therapeutic antibodies targeting the amino terminal of Aβ and that metals effect on lipid oxidation and lipid modification of Aβ could raise concerns on emerging anti-AD treatments with metal chelators. Show more

Keywords: Alzheimer's disease, amyloid-β, free radicals, hydrazide, 4-hydroxy-2-nonenal, immunohistochemistry, oxidative stress

DOI: 10.3233/JAD-2010-100960

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 593-607, 2010

Authors: Ji, Lina | Chauhan, Ved | Mehta, Pankaj | Wegiel, Jerzy | Mehta, Sangita | Chauhan, Abha

Article Type: Research Article

Abstract: Gelsolin plays an important role in the fibrillogenesis of amyloid-β (Aβ). It binds to Aβ and inhibits its fibrillization. Gelsolin also gets proteolytically cleaved under apoptotic conditions. We recently reported a correlation between proteolytic product of gelsolin (carboxyl-terminal fragment of gelsolin, gelsolin-CTF) and severity of Alzheimer's disease. In this study, we report that gelsolin is cleaved in the brains of adult individuals (age, 43–63 years) with Down syndrome (DS), and that levels of gelsolin-CTF are significantly increased in the frontal cortex of adult DS subjects as compared to age-matched control subjects. Gelsolin-CTF was not observed in frontal cortex of young …DS (age 0.5–23 years) and age-matched control subjects. In addition, the levels of both soluble and total Aβ40 and Aβ42 were significantly increased in the frontal cortex of adult DS patients as compared to age-matched control subjects. A positive relationship was observed between gelsolin-CTF in frontal cortex of DS, and the levels of soluble Aβ40 (r2 = 0.7820, p < 0.01) and Aβ42 (r2 = 0.8179, p < 0.01). Experiments with recombinant full-length gelsolin and its N-terminal and C-terminal fragments showed that similar to gelsolin, proteolytic fragments of gelsolin can also interact with soluble synthetic Aβ. The post-translational modification of gelsolin proteins may not be essential as these proteins (overexpressed in Escherichia coli) were able to form complexes with Aβ. These results suggest that there may be a relationship between proteolytic cleavage of gelsolin and increased Aβ in the brain. Since soluble non-fibrillar forms of Aβ are neurotoxic, they may be involved in apoptosis and proteolysis of gelsolin. Show more

Keywords: Alzheimer's disease, amyloid-β protein, apoptosis, carboxyl-terminal fragment of gelsolin, Down syndrome

DOI: 10.3233/JAD-2010-101029

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 609-617, 2010

Authors: Subramanian, Sandhya | Ayala, Patricia | Wadsworth, Teri L. | Harris, Christopher J. | Vandenbark, Arthur A. | Quinn, Joseph F. | Offner, Halina

Article Type: Research Article

Abstract: The inflammatory status of the brain in patients as well as animal models of Alzheimer's disease (AD) has been extensively studied. Accumulation of activated microglia producing tumor necrosis factor-α and monocyte chemotactic protein-1 contribute to the pathology of the disease. However, little is known about the changes in the spleen and associated peripheral immunity that might contribute to AD pathology. The goal of this study was to characterize phenotypic and functional changes in spleen, blood and brain cell populations that contribute to development of an AD-like disease in a triple transgenic (3xTg-AD) mouse model. The 3xTg-AD mice had increased percentages …of brain Gr-1+ granulocytes, dendritic cells and macrophages, spleen and blood derived CD8+Ly6C+ memory T cells and CCR6+ B cells, as well as increased levels of secreted interleukin-6. Brain tissue from older 12 month old symptomatic 3xTg-AD female mice exhibited highly elevated mRNA expression of CCR6 compared to wild-type mice. Importantly, this pronounced increase in expression of CCR6 was also detected in brain and spleen tissue from pre-symptomatic 5–6 month old 3xTg-AD females and males. Our data demonstrate increased expression of CCR6 in the brain and peripheral immune organs of both pre-symptomatic and symptomatic 3xTg-AD mice, strongly suggesting an ongoing inflammatory process that precedes onset of clinical AD-like disease. Show more

Keywords: 3xTg-AD Mice, Alzheimer's Disease, CCR6, inflammation

DOI: 10.3233/JAD-2010-100852

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 619-629, 2010

Authors: Ginsberg, Stephen D. | Mufson, Elliott J. | Counts, Scott E. | Wuu, Joanne | Alldred, Melissa J. | Nixon, Ralph A. | Che, Shaoli

Article Type: Research Article

Abstract: Endocytic alterations are one of the earliest changes to occur in Alzheimer's disease (AD), and are hypothesized to be involved in the selective vulnerability of specific neuronal populations during the progression of AD. Previous microarray and real-time quantitative PCR experiments revealed an upregulation of the early endosomal effector rab5 and the late endosome constituent rab7 in the hippocampus of people with mild cognitive impairment (MCI) and AD. To assess whether these select rab GTPase gene expression changes are reflected in protein levels within selectively vulnerable brain regions (basal forebrain, frontal cortex, and hippocampus) and relatively spared areas (cerebellum and striatum), …we performed immunoblot analysis using antibodies directed against rab5 and rab7 on postmortem human brain tissue harvested from cases with a premortem clinical diagnosis of no cognitive impairment (NCI), MCI, and AD. Results indicate selective upregulation of both rab5 and rab7 levels within basal forebrain, frontal cortex, and hippocampus in MCI and AD, which also correlated with Braak staging. In contrast, no differences in protein levels were found in the less vulnerable cerebellum and striatum. These regional immunoblot assays are consistent with single cell gene expression data, and provide protein-based evidence for endosomal markers contributing to the vulnerability of cell types within selective brain regions during the progression of AD. Show more

Keywords: Basal forebrain, cerebellum, endosome, frontal cortex, hippocampus, mild cognitive impairment, rab GTPase, selective vulnerability, striatum

DOI: 10.3233/JAD-2010-101080

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 631-639, 2010

Authors: Ill-Raga, Gerard | Ramos-Fernández, Eva | Guix, Francesc X. | Tajes, Marta | Bosch-Morató, Mónica | Palomer, Ernest | Godoy, Juan | Belmar, Sebastián | Cerpa, Waldo | Simpkins, James W. | Inestrosa and, Nibaldo C. | Muñoz, Francisco J.

Article Type: Research Article

Abstract: Different mechanisms including oxidative stress are proposed for amyloid-β peptide (Aβ) neurotoxicity, and here we contribute to demonstrate that nitro-oxidative stress is playing a key role. Yeasts are a well-known model for H2 O2 toxicity. Interestingly, yeast cell wall prevents interaction of Aβ fibrils with membrane receptors or calcium channels and we found a significant viability reduction in yeasts when challenged with Aβ fibrils. Furthermore, iron and copper chelators, as well as the antioxidants glutathione and trolox, were neuroprotective on neuroblastoma cells and mouse hippocampal neurons challenged with Aβ fibrils. Glutathione prevents the oxidation, glycation and nitrotyrosination of cell …proteins induced by Aβ. Trolox protected neurons in cell viability studies, maintaining the vesicular transport integrity and preventing the trigger of apoptotic mechanisms. Interestingly, we have also found that brain derived neuronal factor (BDNF) and neurotrophin-3 (NT-3) were able to protect mouse hippocampal and cortical neurons against H2 O2 and Aβ fibrils. Considering that superoxide anion, produced by Aβ cell damage, and nitric oxide, whose production is altered in AD, react to form the highly reactive peroxynitrite anion, we studied the role of trolox to ameliorate the peroxynitrite cell damage. Finally, one of the major proteins to be nitrotyrosinated in AD, the triose phosphate isomerase (TPI) was assayed searching for a denitrase activity that could reverse intracellular nitrotyrosination. We have found that human neuroblastoma SH-SY5Y cells express a constitutive denitrase activity that partially denitrated nitro-TPI. Altogether, our results support a key role of nitro-oxidative stress in the neuronal damage induced by Aβ fibrils. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, antioxidants, oxidative stress, peroxynitrite, triose phosphate isomerase

DOI: 10.3233/JAD-2010-100474

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 641-652, 2010

Authors: Wang, Jun | Santa-Maria, Ismael | Ho, Lap | Ksiezak-Reding, Hanna | Ono, Kenjiro | Teplow, David B. | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Aggregation of microtubule-associated protein tau into insoluble intracellular neurofibrillary tangles is a characteristic hallmark of Alzheimer's disease (AD) and other neurodegenerative diseases, including progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, frontotemporal dementias with Parkinsonism linked to chromosome 17, and Pick's disease. Tau is abnormally hyperphosphorylated in AD and aberrant tau phosphorylation contributes to the neuropathology of AD and other tauopathies. Anti-aggregation and anti-phosphorylation are main approaches for tau-based therapy. In this study, we report that a select grape-seed polyphenol extract (GSPE) could potently interfere with the assembly of tau peptides into neurotoxic aggregates. Moreover, oral administration of GSPE significantly …attenuated the development of AD type tau neuropathology in the brain of TMHT mouse model of AD through mechanisms associated with attenuation of extracellular signal-receptor kinase 1/2 signaling in the brain. Show more

Keywords: Aggregation, Alzheimer's disease, hyperphosphorylation, neurofibrillary tangles, tauopathies

DOI: 10.3233/JAD-2010-101074

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 653-661, 2010

Authors: Zhu, Yi-Cheng | Dufouil, Carole | Soumaré, Aïcha | Mazoyer, Bernard | Chabriat, Hugues | Tzourio, Christophe

Article Type: Research Article

Abstract: The clinical significance of dilated Virchow-Robin spaces (dVRS) remains unclear and their impact on cognitive performances has only been reported in small sample studies. Our aim was to assess the association between severity of dVRS and risk of incident dementia and cognitive decline in an elderly cohort. The degree of dVRS in both white matter and basal ganglia were ranked using high-resolution 3D MRI in a population-based sample of 1,778 non-demented participants from 65 to 80 years of age, who had a cerebral MRI at baseline. Cognitive function was assessed and dementia was diagnosed during a 4-year follow-up period. Cox …proportional hazard models were used to examine the association between dVRS degree on a four-level severity score and incident dementia. The relationship between dVRS degree and change in cognition was examined using linear mixed effect models. During 6,135 person-years of follow-up, 27 individuals developed dementia. The highest degree of dVRS was associated with a strong increase in the risk of incident dementia independently of other standard risk factors of dementia, both for dVRS in white matter (HR = 9.8, 95% CI 1.7–55.3) and in basal ganglia (HR = 5.8, 95% CI 1.2–28.4). After further adjustment on white matter hyperintensity volume and brain infarcts, this association remained significant for dVRS in white matter. Higher rate of cognitive decline was found to be related to high degree of dVRS in basal ganglia but not in white matter. These results need confirmation but they suggest that assessment of the severity of dVRS may help identify groups of individuals that are at increased risk of dementia. Show more

Keywords: Dilated Virchow-Robin space, incident dementia, MRI

DOI: 10.3233/JAD-2010-100378

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 663-672, 2010

Authors: Zhou, Bin | Zhao, Qianhua | Teramukai, Satoshi | Ding, Ding | Guo, Qihao | Fukushima, Masanori | Hong, Zhen

Article Type: Research Article

Abstract: We aimed to investigate the natural history of Alzheimer's disease (AD) and the risk factors associated with survival. We performed a 5-year retrospective cohort study on 467 consecutive outpatients clinically diagnosed with AD and treated between January 1, 2003, and December 31, 2006, at Huashan Hospital, Shanghai, China. The primary endpoint in this study was survival. At baseline, we evaluated the patients' demographic characteristics and neuropsychological characteristics, comorbid conditions, neuroimaging findings, complications, and neurological signs. Among the 467 patients, 398 survived. Male gender, age, and disease severity were associated with mortality. Survival analysis using the proportional hazard model with adjustments …for gender, age, and disease stage revealed that the cognition factors that predicted longer survival included high total score [hazard ratio (HR), 0.85; 95% confidence interval (CI), 0.76–0.96] and sub-scores in the verbal fluency test (animals, vegetables, and fruits). The presence of at least 1 complication was an independent factor predictive of a decreased lifespan (HR, 5.55; 95% CI, 1.91–16.13). In AD patients, presence of complications was an indicator of poor survival, while good performance in assessments of executive function, such as the verbal fluency test and Stroop test, at baseline was associated with longer survival. Show more

Keywords: Alzheimer's disease, complications, executive function, prognosis, retrospective longitudinal

DOI: 10.3233/JAD-2010-100318

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 673-682, 2010

Authors: Zhang, Can | Browne, Andrew | DiVito, Jason R. | Stevenson, Jesse A. | Romano, Donna | Dong, Yuanlin | Xie, Zhongcong | Tanzi, Rudolph E.

Article Type: Research Article

Abstract: Mounting evidence suggests that Alzheimer's disease (AD) is caused by the accumulation of the small peptide, amyloid-β (Aβ), a proteolytic cleavage product of amyloid-β protein precursor (AβPP). Aβ is generated through a serial cleavage of AβPP by β- and γ-secretase. Aβ40 and Aβ42 are the two main components of amyloid plaques in AD brains, with Aβ42 being more prone to aggregation. AβPP can also be processed by α-secretase, which cleaves AβPP within the Aβ sequence, thereby preventing the generation of Aβ. Little is currently known regarding the effects of cell density on AβPP processing and Aβ generation. …Here we assessed the effects of cell density on AβPP processing in neuronal and non-neuronal cell lines, as well as mouse primary cortical neurons. We found that decreased cell density significantly increases levels of Aβ40 , Aβ42 , total Aβ, and the ratio of Aβ42 : Aβ40 . These results also indicate that cell density is a significant modulator of AβPP processing. Overall, these findings carry profound implications for both previous and forthcoming studies aiming to assess the effects of various conditions and genetic/chemical factors, e.g., novel drugs on AβPP processing and Aβ generation in cell-based systems. Moreover, it is interesting to speculate whether cell density changes in vivo may also affect AβPP processing and Aβ levels in the AD brain. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, cell density

DOI: 10.3233/JAD-2010-100816

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 683-694, 2010

Article Type: Book Review

DOI: 10.3233/JAD-2010-100841

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 695-695, 2010

Article Type: Announcement

DOI: 10.3233/JAD-2010-101471

Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 697-698, 2010