Journal of Alzheimer's Disease - Volume 30, issue 2

Authors: Borowczyk, Kamila | Shih, Diana M. | Jakubowski, Hieronim

Article Type: Research Article

Abstract: Homocysteine (Hcy)-thiolactone is toxic, induces epileptic seizures in rodents, and has been implicated in Alzheimer's disease. Paraoxonase 1 (Pon1), a component of high-density lipoprotein, hydrolyzes Hcy-thiolactone in vitro. Whether this reflects a physiological function and whether Pon1 can protect against Hcy-thiolactone toxicity was unknown. Here we show that Hcy-thiolactone was elevated in brains of Pon1−/− mice (1.5-fold, p = 0.047) and that Pon1−/− mice excrete more Hcy-thiolactone than wild type animals (2.4-fold, p = 0.047). The frequency of seizures induced by intraperitoneal injections of L-Hcy-thiolactone was significantly higher in Pon1−/− mice compared with wild type animals (52.8% …versus 29.5%, p = 0.042); the latency of seizures was lower in Pon1−/− mice than in wild type animals (31.8 min versus 41.2 min, p = 0.019). Using the Pon1 null mice, we provide the first direct evidence that a specific Hcy metabolite, Hcy-thiolactone, rather than Hcy itself is neurotoxic in vivo. Our findings indicate that Pon1 protects mice against Hcy-thiolactone neurotoxicity by hydrolyzing it in the brain, and suggest a mechanism by which Pon1 can protect against neurodegeneration associated with hyperhomocysteinemia and Alzheimer's disease. Show more

Keywords: Alzheimer's disease, homocysteine thiolactone, neurotoxicity, Pon 1

DOI: 10.3233/JAD-2012-111940

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 225-231, 2012

Authors: Martínez, Eva | Navarro, Ana | Ordóñez, Cristina | del Valle, Eva | Tolivia, Jorge

Article Type: Research Article

Abstract: Apolipoprotein D (ApoD) is a secreted glycoprotein that is markedly induced in several pathological and stressful conditions in the nervous system. In the central nervous system, ApoD expression is upregulated during aging, after traumatic brain injury, and in several human neuropathologies such as Alzheimer's disease (AD), where it is found associated with amyloid-β (Aβ) plaques. Recent studies have indicated that ApoD has an important function as a neuroprotective and antioxidant protein. The aim of this work is to study the effect of the peptide fragment Aβ25-35 , which is believed to play a major role in the neurodegenerative process of …AD, in ApoD expression in a mouse hippocampal cell line. In addition, we studied whether direct addition of exogenous human recombinant ApoD protein has neuroprotective effect against Aβ25-35 treatment on neuronal cells. Our results demonstrate that Aβ25-35 induces ApoD expression in hippocampal cells in response to stress-induced growth arrest. This observed relationship between Aβ and ApoD expression could explain the elevated levels of ApoD found in AD brain, where it may be a neuroprotective molecule in the course of AD, probably related to its lipid transport function or a direct antioxidant property. However, the addition of exogenous human recombinant ApoD does not exert any protective effect, most likely due to its major structural modifications. Show more

Keywords: Alzheimer's disease, amyloid-β$_{25\hbox{-}35}$, apolipoprotein D, growth arrest, HT22, oxidative stress

DOI: 10.3233/JAD-2012-112102

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 233-244, 2012

Authors: Neumeister, Katharina L. | Riepe, Matthias W.

Article Type: Research Article

Abstract: Current treatment of Alzheimer's disease rests on cholinergic and anti-glutamatergic substances. It has been suggested that acetylcholine is required for memory acquisition but is less important for memory retrieval. It was our goal to investigate the effects of treatment with donepezil, memantine, and a combination thereof on spatial memory. We assessed spatial memory of male wild type and B6C3-Tg(APPswe,PSEN1dE9)85Dbo (APP23) transgenic animals in a complex dry-land maze. Animals were treated with donepezil (1 mg/kg) and memantine (10 mg/kg). Total time to escape from the maze decreased in 4.5 month old sham-treated wild-type animals and, to a lesser extent, in APP23 …animals. Analysis of time spent moving and resting revealed that the treatment effect is conferred by a reduction of the moving time for donepezil and a reduction of the resting time for memantine. Combination treatment with donepezil and memantine fostered a greater improvement than treatment with either substance alone. We conclude that enhancement of spatial learning in a dry-land maze on cholinergic or anti-glutamatergic treatment is differentially conferred during moving of the animals, possibly reflecting acquisition of spatial information, and resting of the animals, possibly reflecting retrieval of spatial information. Combination treatment with donepezil and memantine exerts a synergistic effect improving both moving time and resting time and thus possibly both spatial learning and retrieval. Show more

Keywords: Alzheimer's disease, awake immobility, donepezil, maze, memantine, spatial learning, transgenic animal model

DOI: 10.3233/JAD-2012-111643

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 245-251, 2012

Authors: Whalley, Lawrence J. | Sharma, Sumit | Fox, Helen C. | Murray, Alison D. | Staff, Roger T. | Duthie, Ashleigh C. | Deary, Ian J. | Starr, John M.

Article Type: Research Article

Abstract: Impaired cognitive function associated with use of anticholinergic drugs may be partly attributed to underlying physical illness and exposure to factors that increase the risk of some physical disorders such as low socioeconomic status (SES) and less education. To estimate the extent of cognitive impairment and risk of progress to dementia associated with anticholinergic drug use and to estimate confounding by gender, APOE, family history of dementia, lower SES, less education, and lower childhood mental ability, we recruited 281 volunteers at age 77-78 without overt dementia who had taken part in the Scottish Mental Survey of 1932. Clinical histories, use …of medications, self reported frequency of emotional symptoms and standardized tests of cognitive function were obtained. With and without adjustment for age and childhood IQ, there were significant between-group differences in tests of non-verbal reasoning and spatial ability. During 10 year follow-up, progress to overt dementia was not associated with anticholinergic drugs use on recruitment but female gender and a history of dementia in parent or sibling were associated with dementia. We concluded that anticholinergic drug use in this narrow age range sample was linked to cognitive impairment but not to subsequent dementia. Show more

Keywords: Aberdeen 1921 birth cohort, aging, anticholinergic, APOE, childhood intelligence, cognitive function, dementia, drug, family history

DOI: 10.3233/JAD-2012-110935

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 253-261, 2012

Authors: Yu, Yan | Zhou, Liang | Sun, Miao | Zhou, Ting | Zhong, Kaiyin | Wang, Hecheng | Liu, Yi | Liu, Xinying | Xiao, RuiZhong | Ge, Jia | Tu, PengFei | Fan, Dong Sheng | Lan, Yuan | Hui, Chen | Chui, Dehua

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptide, which can invoke a cascade of inflammatory responses, is considered to play a causal role in the development and progress of Alzheimer's disease (AD). Xylocoside G (XG) is an active compound isolated from a traditional Chinese medicinal plant, Itoa orientalis. We have previously reported that XG has neuroprotective effects, of which the mechanism is yet unknown. In this study, we investigated the possible mechanisms underlying neuroprotection of XG against Aβ-induced toxicity in SH-SY5Y cells and primary neurons. Pretreatment with XG significantly attenuated the cell viability reduction induced by Aβ exposure in a dose dependent manner which was …testified by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release assay. In addition, pretreatment with XG countered the effect of Aβ on Bax and Bcl-2 expression and repressed Aβ-induced caspase-3 activation, suggesting that the neuroprotective effect of XG is associated with apoptosis regulation. Neuroinflammation has been implicated in Aβ-induced neuronal death. XG significantly attenuated Aβ-stimulated release of inflammatory factors such as tumor necrosis factor-α, interleukin-1β, and prostaglandin E2 . It also downregulated the expression of cyclooxygenase-2 in SH-SY5Y cells. Further molecular mechanism studies demonstrated that XG inhibited Aβ-induced NF-κB p65 translocation, which was probably the result of inhibition of JNK phosphorylation but not ERK or p38 MAPK pathway by XG. This is the first study to demonstrate that XG protects SH-SY5Y cells against Aβ-induced inflammation and apoptosis by down-regulating NF-κB signaling pathways. Show more

Keywords: Amyloid-β, apoptosis, MAPK, NF-κB, neuroinflammation, Xylocoside G

DOI: 10.3233/JAD-2012-110779

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 263-275, 2012

Authors: Pastorino, Lucia | Ma, Suk Ling | Balastik, Martin | Huang, Pengyu | Pandya, Darshan | Nicholson, Linda | Lu, Kun Ping

Article Type: Research Article

Abstract: Increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) is a characteristic of Alzheimer's disease (AD). We previously observed that the prolyl isomerase Pin1, which is down-regulated in AD, regulates AβPP conformation accelerating cis/trans isomerization of the phospho-Thr668-Pro669 peptide bond, and that Pin1 knockout in mice increases the amyloidogenic processing of AβPP, although the underlying mechanism is still unknown. Since the intracellular localization of AβPP determines whether the processing will be amyloidogenic or non-amyloidogenic, here we addressed the question whether loss of Pin1 function affects the intracellular localization of AβPP, influencing AβPP processing. Using cellular models of Pin1 knockout and …Pin1 knockdown, we have demonstrated that lowering Pin1 levels changed the intracellular localization and the processing of AβPP. Under these conditions, less AβPP was retained at the plasma membrane favoring the amyloidogenic processing, and the kinetics of AβPP internalization increased as well as the nuclear trafficking of AβPP C-terminal fragment AICD. In addition, AβPPThr668Ala mutant, which cannot bind to Pin1 and retains more trans conformation, rescued the levels of AβPP at the plasma membrane in Pin1 knockout cells. Thus, loss of Pin1 function contributes to amyloidogenic pathways, by facilitating both the removal of AβPP from compartments where it is mostly non-amyloidogenic and its internalization to more amyloidogenic compartments. These data suggest that physiological levels of Pin1 are important to control the intracellular localization and metabolic fate of Thr668-phosphorylated AβPP, and regulation of AβPP conformation is especially important in pathologic conditions of AβPP hyperphosphorylation and/or loss of Pin1 function, associated with AD. Show more

Keywords: Conformation, internalization, phosphorylation, prolyl isomerase

DOI: 10.3233/JAD-2012-111259

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 277-297, 2012

Authors: Ravona-Springer, Ramit | Moshier, Erin | Schmeidler, James | Godbold, James | Akrivos, Jimmy | Rapp, Michael | Grossman, Hillel T. | Wysocki, Michael | Silverman, Jeremy M. | Haroutunian, Vahram | Beeri, Michal Schnaider

Article Type: Research Article

Abstract: The aim of the present study was to examine the relationship of changes in long term glucose levels as measured by Hemoglobin A1c (HbA1c) with simultaneous changes in cognition. The sample included in the present analysis consisted of 101 community dwelling non-diabetic elderly subjects participating in ongoing longitudinal studies of cognition. Subjects were included in this study if they were cognitively normal at baseline, had at least one co-temporaneous follow-up assessment of HbA1c and the Mini Mental State Exam (MMSE), and complete data on age, gender, race, and years of education. MMSE decline over time was the main outcome measure. …In TOBIT mixed regression models, MMSE was the dependent variable and HbA1c the time-varying covariate. Sociodemographic (age, gender, and education), cardiovascular (hypertension and APOE4 status), and lifestyle (smoking and physical activity) covariates were included in the statistical model. After adjusting for age at follow-up, there was a decrease of 1.37 points in the MMSE (p = 0.0002) per unit increase in HbA1c. This result remained essentially unchanged after adjusting also for gender and education (p = 0.0005), cardiovascular factors (p = 0.0003), and lifestyle (p = 0.0006). Additionally, results remained very similar after excluding subjects with potentially incipient diabetes with HbA1c between 6 and 7. These findings suggest that in non-diabetic non-demented elderly subjects, an increase in HbA1c over time is associated with cognitive decline. Such results may have broad clinical applicability since manipulation of glucose control, even in non-diabetics, may affect cognitive performance, perhaps enabling preventive measures against dementia. Show more

Keywords: Cognition, elderly, glucose control, HbA1c, non-diabetic

DOI: 10.3233/JAD-2012-120106

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 299-309, 2012

Authors: Zabel, Matthew | Schrag, Matthew | Mueller, Claudius | Zhou, Weidong | Crofton, Andrew | Petersen, Floyd | Dickson, April | Kirsch, Wolff M.

Article Type: Research Article

Abstract: Because of the growing impact of late onset cognitive loss, considerable effort has been directed toward the development of improved diagnostic techniques for Alzheimer's disease (AD) that may pave the way for earlier (and more effective) therapeutic efforts. Serum-based biomarkers are the least expensive and invasive modality for screening and routine monitoring. We systematically reviewed the literature to assemble a list of serum biomarkers relevant to AD. In parallel, we conducted a proteomic LC-MS/MS analysis of serum collected from neurologically normal subjects and subjects with mild cognitive impairment (MCI) and early AD (n = 6 in all). Complement C3 and …alpha-2-macroglobulin were identified from both the literature review and our proteomic screen for further validation. For these two candidates, ELISA was performed on serum collected from a small independent cohort of subjects for longitudinal analysis. Serum was serially collected from neurologically normal subjects (n = 5) and subjects with MCI who were subsequently followed for a period of two years (n = 5) and regrouped into stable MCI and progressive MCI or AD (n = 6). The ability of each marker to predict which subjects with MCI would progress to dementia and which would remain cognitively stable was assessed. Patients with probable cerebral amyloid angiopathy were also identified (n = 3). This preliminary analysis tested the most-promising serum protein biomarkers for AD and we concluded that none are yet ready for use in the clinical diagnosis and management of dementia. However, a more thorough assessment in longitudinal studies with higher statistical power is warranted. Show more

Keywords: Alpha1-antichymotrypsin, C1 inhibitor, cerebral amyloid angiopathy, complement C4, plasma, prospective

DOI: 10.3233/JAD-2012-112012

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 311-321, 2012

Authors: Watt, Andrew D. | Perez, Keyla A. | Rembach, Alan R. | Masters, Colin L. | Villemagne, Victor L. | Barnham, Kevin J.

Article Type: Research Article

Abstract: Effective therapeutic interventions for Alzheimer's disease (AD) will require treatment regimes to move toward the earliest stages of the disease. For this to occur the field has to identify biomarkers that are able to accurately identify individuals at risk for progression toward AD in the presymptomatic stage. One very significant implication is that some form of population-based screening will need to be undertaken in order to identify those at risk. To date, efforts in neuroimaging brain amyloid-β (Aβ) and changes in cerebrospinal fluid Aβ and tau levels shows promise, however, it is questionable as to whether these methods are applicable …for screening the general population. The Aβ peptide is also found in blood which is the most economical and efficient biological fluid to analyze. Unfortunately, investigations into blood-based diagnostic markers have produced mixed results. This variability is likely to be the result of differences in the preanalytical processing of samples and as such is delaying progress in the field. Reported preanalytical processing techniques from 87 recent articles focusing on the measurement of Aβ in blood were compared, to investigate whether basic sample-handling techniques were comparable between studies. This comparison revealed that not only is it likely that some of the variability in blood-based results is attributable to discrepancies in preanalytical methodologies but also that the field is failing to adequately report sample processing techniques. This review highlights the current shortcomings in methodological reporting and recommends a standardized blood collection methodology based on the limited consensus of the reviewed articles. Show more

Keywords: Alzheimer's disease, amyloid-β, biomarkers, blood, plasma, protocol, standardized

DOI: 10.3233/JAD-2012-120058

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 323-336, 2012

Authors: Esteras, Noemí | Alquézar, Carolina | Bartolomé, Fernando | Antequera, Desiree | Barrios, Laura | Carro, Eva | Cerdán, Sebastián | Martín-Requero, Ángeles

Article Type: Research Article

Abstract: Murine models of Alzheimer's disease (AD) provide means to detect and follow biomarker changes similar to those observed in humans. Non-invasive biomarkers, such as those provided by magnetic resonance imaging (MRI) and spectroscopy (MRS) methods are highly desirable, however, systematic studies of in vivo MRI/MRS methods to characterize the cerebral morphology and metabolic pattern of these mice remain scarce. We investigated sixteen consecutive slices from the brain of wild-type and AβPP/PS1 mice, obtaining a collection of T2 weighted, diffusion weighted and magnetization transfer weighted images as well as 1 H PRESS spectra from the cortical and subcortical areas. Compared …to controls, AβPP/PS1 mice show significant regional hyperintensities in T2 weighted images of the cerebral cortex, significant ventricular enlargement, and decreased hippocampal area and fractional magnetization transfer. MRS demonstrated an increase in the ratio of choline (Cho) to creatine (Cr) in the cortical and subcortical areas of the transgenic animals. A logistic regression classifier was implemented considering all parameters investigated, and revealed the most characteristic changes and allowed for the correct classification of control and AβPP/PS1 mice. In summary, the present results provide a useful frame to evaluate optimal MRI/MRS biomarkers for the characterization of AD models, potentially applicable in drug discovery processes, because of their non-invasive and repeatable nature in longitudinal studies. Show more

Keywords: ADC maps, Alzheimer's disease, MRI, MRS, MT maps, T2-weighting, transgenic mice, ventricle enlargement

DOI: 10.3233/JAD-2012-111967

Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 337-353, 2012