Journal of Alzheimer's Disease - Volume 31, issue 1

Authors: Liu, Yanyong | Aisa, Haji Akber | Ji, Chao | Yang, Nan | Zhu, Haibo | Zuo, Pingping

Article Type: Research Article

Abstract: Aging-associated cognitive impairment is an important health care issue since individuals with mild cognitive impairment are more likely to develop Alzheimer’s disease. In the present study, the protective effect of Gossypium herbaceam extracts (GHE) on learning and memory impairment associated with aging were examined in vivo using Morris water maze and step through task. Furthermore, the antioxidant activity and neuroprotective effect of GHE was investigated with methods of histochemistry and biochemistry. These data showed that oral administration with GHE at the doses of 35, 70, and 140 mg/kg exerted an improved effect on the learning and memory impairment in …aged rats. Subsequently, GHE afforded a beneficial action on eradication of free radicals without influence on the activity of glutathione peroxidase and superoxide dismutase. GHE treatment enhanced the expression levels of nerve growth factor. Meanwhile, proliferation of neural progenitor cells was elevated in hippocampus after treatment with GHE. Taken together, neurogenic niche improvement could be involved in the mechanism underlying neuroprotection of GHE against aging-associated cognitive impairment. These findings suggested that GHE might be a potential agent as cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer’s disease or treatment of aging-associated cognitive impairment. Show more

Keywords: Aging, Alzheimer’s disease, mild cognitive impairment, oxidative stress

DOI: 10.3233/JAD-2012-112153

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 101-111, 2012

Authors: Saiz-Sanchez, Daniel | Ubeda-Bañon, Isabel | De la Rosa-Prieto, Carlos | Martinez-Marcos, Alino

Article Type: Research Article

Abstract: Impaired olfaction is an early symptom of Alzheimer's disease (AD). Neuroanatomical changes underlying this deficit in the olfactory system are largely unknown. Cell neurodegeneration is known to involve, among others, somatostatin (SST)- and calcium-binding protein-positive cells. We report here quantitative analysis of temporal changes in the distribution of interneuron cell populations in the olfactory cortex of an AβPP/PS1 double-transgenic mouse model of AD and its correlation with amyloid-β pathology. To investigate early stages of pathology, the piriform and lateral entorhinal cortices were analyzed in groups of homozygous AβPP/PS1 and control animals at 2, 4, 6, and 8 months of age. …There was a significant increase in brain levels of aggregated amyloid-β peptide with age, accompanied by an early and marked fall in numbers of SST- and calretinin-positive interneurons; a later and less pronounced decrease in levels of calbindin- and parvalbumin-positive cells was also observed. In addition, double-labeling experiments indicated high levels of co-localization of SST-positive cells with amyloid-β expression in olfactory areas. These observations argue that SST-positive cells are vulnerable to amyloid-β neuropathy in the olfactory cortex during the early stages of AD. These data may cast light on the neural basis of hyposmia associated with this disorder and on the mechanisms of cell vulnerability to neurodegeneration. Show more

Keywords: Alzheimer's disease, amyloid, calcium-binding protein, entorhinal cortex, interneuron, piriform cortex, somatostatin, transgenic

DOI: 10.3233/JAD-2012-111889

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 113-129, 2012

Authors: Yang, Ling | Ye, Chun-yan | Huang, Xiao-tian | Tang, Xi-can | Zhang, Hai-yan

Article Type: Research Article

Abstract: A number of recent discoveries indicate that huperzine A, an active herbal medicine employed for the treatment of Alzheimer's disease (AD) in China, can afford neuroprotection on in vitro and in vivo models related to mitochondrial dysfunction. However, it is an intricate and highly debated research topic about whether another pharmacological mechanism is involved in the beneficial profiles of huperzine A, independent of its well-recognized potent acetycholinesterase (AChE) inhibitory effect. As an extension, this study for the first time verified the co-occurrence of the beneficial effects of huperzine A on mitochondrial dysfunction and memory deficits in AβPP/PS1 double transgenic mice, …at a time point that AChE was not inhibited. Moreover, using isolated brain cortical mitochondria, we confirmed the ameliorating effect of huperzine A on oligomeric Aβ1-42 -induced ATP reduction and mitochondrial swelling, as well as a decrease in the enzymatic activities of respiratory chain complexes, especially complex II-III and complex IV, which may be attributed to the blockage of oligomeric Aβ1-42 from penetrating into mitochondria. These results shed more light on a potential direct target of huperzine A on isolated mitochondria, which may be largely different from its specific inhibition on AChE. This work describes a novel mechanism of neuroprotection by huperzine A and provides important clues for discovering novel therapeutic strategy for AD. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, huperzine A, mitochondrial dysfunction, oligomer

DOI: 10.3233/JAD-2012-120274

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 131-142, 2012

Authors: Chow, Tiffany W. | Fridhandler, Jonathan D. | Binns, Malcolm A. | Lee, Albert | Merrilees, Jennifer | Rosen, Howie J. | Ketelle, Robin | Miller, Bruce L.

Article Type: Research Article

Abstract: Predicting the progression of dementia is a challenge for clinicians yet this information is highly valued by patients' families. An informally observed 4-stage model of dementia can be helpful in educating caregivers and preparing them for what lies ahead. In the behavioral variant of frontotemporal dementia (bvFTD), this model describes the evolution of behavioral disturbances and is characterized by an inflection point between stage 2 (progressively severe behavioral aberration) and stage 3 (increasing apathy and remission of behavior problems). In this study, we sought evidence for this model using a database of serial Neuropsychiatric Inventory (NPI) scores for 45 patients …with FTD and 47 patients with Alzheimer's disease (AD). We transformed the NPI scores into a single variable for each participant that represented the yearly rate of change in total NPI score and used this as the dependent variable in a multivariate linear regression. Age at onset of dementia, NPI score at initial visit, and duration of illness at first NPI all contributed significantly to the regression model in the bvFTD group. Participants with an initial NPI acquired before 6 years of disease duration tended to have a more positive rate of change in NPI total score (representing worsening behavioral disturbances) than those with an initial NPI performed after 6 years. None of the aforementioned variables were significantly associated with yearly change in NPI total score in the AD group. These results support a crescendo-decrescendo trajectory of behavioral symptoms in bvFTD but do not suggest that there is a similar pattern in AD, and further longitudinal data collection is necessary. Show more

Keywords: Agitation, Alzheimer's disease, apathy, behavioral symptoms, disease progression, frontotemporal dementia, longitudinal study, neurobehavioral manifestations

DOI: 10.3233/JAD-2012-111916

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 143-149, 2012

Authors: Qosa, Hisham | Abuznait, Alaa H. | Hill, Ronald A. | Kaddoumi, Amal

Article Type: Research Article

Abstract: Rifampicin and caffeine are widely used drugs with reported protective effect against Alzheimer's disease (AD). However, the mechanism underlying this effect is incompletely understood. In this study, we have hypothesized that enhanced amyloid-β (Aβ) clearance from the brain across the blood-brain barrier (BBB) of wild-type mice treated with rifampicin or caffeine is caused by both drugs potential to upregulate low-density lipoprotein receptor related protein-1 (LRP1) and/or P-glycoprotein (P-gp) at the BBB. Expression studies of LRP1 and P-gp in brain endothelial cells and isolated mice brain microvessels following treatment with rifampicin or caffeine demonstrated both drugs as P-gp inducers, and only …rifampicin as an LRP1 inducer. Also, brain efflux index (BEI%) studies conducted on C57BL/6 mice treated with either drug to study alterations in Aβ clearance demonstrated the BEI% of Aβ in rifampicin (82.4 ± 4.3%) and caffeine (80.4 ± 4.8%) treated mice were significantly higher than those of control mice (62.4 ± 6.1%, p < 0.01). LRP1 and P-gp inhibition studies confirmed the importance of both proteins to the clearance of Aβ, and that enhanced clearance following drugs treatment was caused by LRP1 and/or P-gp upregulation at the mouse BBB. Furthermore, our results provided evidence for the presence of a yet to be identified transporter/receptor that plays significant role in Aβ clearance and is upregulated by caffeine and rifampicin. In conclusion, our results demonstrated the upregulation of LRP1 and P-gp at the BBB by rifampicin and caffeine enhanced brain Aβ clearance, and this effect could explain, at least in part, the protective effect of rifampicin and caffeine against AD. Show more

Keywords: Alzheimer's disease, amyloid-β, caffeine, LRP1, P-gp, rifampicin

DOI: 10.3233/JAD-2012-120319

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 151-165, 2012

Authors: Joshi, Yash B. | Chu, Jin | Praticò, Domenico

Article Type: Research Article

Abstract: Several studies have linked stress with Alzheimer's disease (AD) vulnerability; however, the mechanism remains to be fully elucidated. In the current paper, we investigated the role of glucocortitcoids on the AD-like phenotype. We administered the glucocorticoid dexamethasone to Tg2576 mice for 4 weeks and then investigated its effect on memory, amyloid-β and tau levels, and metabolism. At the end of the treatment period, we observed that mice receiving dexamethasone had a significant impairment in the fear conditioning paradigm compared with controls. Dexamethasone-treated animals showed a significant increase in the amount of brain soluble Aβ40 levels, but no alteration in …the steady state levels of its precursor protein, AβPP, or in the major protease enzymes involved in its metabolism (i.e., ADAM-10, BACE-1, or γ-secretase complex). While total tau protein levels were unaltered between the two groups, we found that dexamethasone significantly reduced tau phosphorylation at specific sites that were mediated by decreases in glycogen synthase kinase-3β protein level activity. Finally, we observed a direct correlation between memory impairments and tau phosphorylation levels. Our study highlights the significant role that glucocorticoids play in exacerbating AD-like cognitive impairments via alteration of tau protein phosphorylation state. Show more

Keywords: Alzheimer's disease, transgenic animal model, stress, glucocorticoid

DOI: 10.3233/JAD-2012-120328

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 167-176, 2012

Authors: Realmuto, Sabrina | Cinturino, Antonio | Arnao, Valentina | Mazzola, Maria Antonietta | Cupidi, Chiara | Aridon, Paolo | Ragonese, Paolo | Savettieri, Giovanni | D'Amelio, Marco

Article Type: Research Article

Abstract: Studies reporting an inverse association between Alzheimer's disease (AD) and cancer are scant. Available data are mostly based on ancillary findings of mortality data or obtained from studies evaluating frequency of neoplasms in AD patients independently if they occurred before or after AD. Moreover, some studies estimated frequencies of neoplasms in demented individuals, who were not necessarily AD patients. We estimated frequency of tumors preceding the onset of AD in AD patients and compared it to that of age- and gender-matched AD-free individuals. Occurrence of tumors preceding AD onset was assessed through a semi-structured questionnaire. Tumors were categorized as benign, …malignant, or of uncertain classification and as endocrine-related or not. Odds ratios (OR), used as measure of the association between the two diseases, were adjusted for tumor categories and known risk factors for AD and tumors. We included 126 AD patients and 252 matched controls. Tumor frequency before AD onset was 18.2% among cases and 24.2% among controls. There was a suggestive trend of an overall inverse association between the two diseases (adjusted OR 0.6; 95% CI 0.4–1.1; p = 0.11). Risk for neoplasms was significantly reduced only for women (adjusted OR, 0.5; 95% CI 0.3–0.9; p = 0.03) and for endocrine related tumors (adjusted OR, 0.5; 95% CI 0.2–1; p = 0.04). Our study confirms the inverse association reported in previous epidemiological studies. Though our findings might be explained by processes playing an opposite role in tumors development and neurodegeneration, they are also suggestive for a possible role of estrogen. Show more

Keywords: Aging, Alzheimer's disease, case-control, estrogen, neurodegeneration, tumors

DOI: 10.3233/JAD-2012-120184

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 177-182, 2012

Authors: Calderón-Garcidueñas, Lilian | Mora-Tiscareño, Antonieta | Styner, Martin | Gómez-garza, Gilberto | Zhu, Hongtu | Torres-Jardón, Ricardo | Carlos, Esperanza | Solorio-López, Edelmira | Medina-Cortina, Humberto | Kavanaugh, Michael | D'Angiulli, Amedeo

Article Type: Research Article

Abstract: Air pollution exposures are linked to neuroinflammation and neuropathology in young urbanites. Forty percent of exposed children and young adults exhibit frontal tau hyperphosphorylation and 51% have amyloid-β diffuse plaques compared to 0% in low pollution controls. In older adults, white matter hyperintensities (WMH) are associated with cognitive deficits while inflammatory markers correlate with greater atrophy than expected for age. We investigated patterns of WMH, magnetic resonance imaging (MRI) volume growth, blood inflammatory mediators, and cognition in matched children from two urban cohorts: one severely and one minimally exposed to air pollution. Baseline and one year follow-up measurements of cognitive …abilities, brain MRI volumes, and blood were collected in 20 Mexico City (MC) children (10 with WMH+ , and 10 without WMH− ) and 10 matched controls (WMH− ). MC WMH− children display the profile of classical pro-inflammatory defensive responses: high interleukin 12, production of powerful pro-inflammatory cytokines, and low concentrations of key cytokines and chemokines associated with neuroprotection. MC WMH+ children exhibit a response involved in resolution of inflammation, immunoregulation, and tissue remodeling. The MC WMH+ group responded to the air pollution-associated brain volumetric alterations with white and grey matter volume increases in temporal, parietal, and frontal regions and better cognitive performance compared to MC WMH− . We conclude that complex modulation of cytokines and chemokines influences children's central nervous system structural and volumetric responses and cognitive correlates resulting from environmental pollution exposures. Identification of biomarkers associating systemic inflammation to brain growth is critical for detecting children at higher risk for cognitive deficits and neurodegeneration, thereby warranting early implementation of neuroprotective measures. Show more

Keywords: Air pollution, Alzheimer's disease risk, biomarkers, chemokines, children, cognition, cytokines, fine particulate matter, MRI volumes, systemic inflammation, white matter hyperintensities

DOI: 10.3233/JAD-2012-120610

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 183-191, 2012

Authors: Wang, Shu | Qaisar, Uzma | Yin, Xiangling | Grammas, Paula

Article Type: Research Article

Abstract: The enigma that is Alzheimer's disease (AD) continues to present daunting challenges for effective therapeutic intervention. The lack of disease-modifying therapies may, in part, be attributable to the narrow research focus employed to understand this complex disease. Most studies into disease pathogenesis are based on a priori assumptions about the role of AD lesion-associated proteins such as amyloid-β and tau. However, the complex disease processes at work may not be amenable to single-target therapeutic approaches. Genome-wide expression studies provide an unbiased approach for investigating the pathogenesis of complex diseases like AD. A growing literature suggests a role for cerebrovascular contributions …to the pathogenesis of AD. The objective of the current study is to examine human brain microvessels isolated from AD patients and controls by microarray analysis. Differentially expressed genes with more than 2-fold change are used for further data analysis. Gene ontology analysis and pathway analysis algorithms within GeneSpringGX are employed to understand the regulatory networks of differentially expressed genes. Twelve matched pairs of AD and control brain microvessel samples are hybridized to Agilent Human 4 × 44 K arrays in replication. We document that more than 2,000 genes are differentially altered in AD microvessels and that a large number of these genes map to pathways associated with immune and inflammatory response, signal transduction, and nervous system development and function categories. These data may help elucidate heretofore unknown molecular alterations in the AD cerebromicrovasculature. Show more

Keywords: Alzheimer's disease, brain, gene expression profile, microarray, microvessel

DOI: 10.3233/JAD-2012-120454

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 193-205, 2012

Authors: Hwang, Sung Hee | Shin, Eun-Joo | Shin, Tae-Joon | Lee, Byung-Hwan | Choi, Sun-Hye | Kang, Jiyeon | Kim, Hyeon-Joong | Kwon, Seung-Hwan | Jang, Choon-Gon | Lee, Jun-Ho | Kim, Hyoung-Chun | Nah, Seung-Yeol

Article Type: Research Article

Abstract: Ginseng extracts show cognition-enhancing effects in Alzheimer's disease (AD) patients. However, little is known about the active components and molecular mechanisms of how ginseng exerts its effects. Recently, we isolated a novel lysophosphatidic acid (LPA) receptor-activating ligand from ginseng, gintonin. AD is caused by amyloid-β protein (Aβ) accumulation. Aβ is derived from amyloid-β protein precursors (AβPPs) through the amyloidogenic pathway. In contrast, non-amyloidogenic pathways produce beneficial, soluble AβPPα (sAβPPα). Here, we describe our investigations of the effect of gintonin on sAβPPα release, Aβ formation, Swedish-AβPP transfection-mediated neurotoxicity in SH-SY5Y neuroblastoma cells, and Aβ-induced neuropathy in mice. Gintonin promoted sAβPPα release …in a concentration- and time-dependent manner. Gintonin action was also blocked by the Ca2+ chelator BAPTA, α-secretase inhibitor TAPI-2, and protein-trafficking inhibitor brefeldin. Gintonin decreased Aβ1-42 release and attenuated Aβ1-40 -induced cytotoxicity in SH-SY5Y cells. Gintonin also rescued Aβ1-40 -induced cognitive dysfunction in mice. Moreover, in a transgenic mouse AD model, long-term oral administration of gintonin attenuated amyloid plaque deposition as well as short- and long-term memory impairment. In the present study, we demonstrated that gintonin mediated the promotion of non-amyloidogenic processing to stimulate sAβPPα release to restore brain function in mice with AD. Gintonin could be a useful agent for AD prevention or therapy. Show more

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

DOI: 10.3233/JAD-2012-120439

Citation: Journal of Alzheimer's Disease, vol. 31, no. 1, pp. 207-223, 2012