Journal of Alzheimer's Disease - Volume 20, issue 1

Authors: De Bartolo, Paola | Cutuli, Debora | Ricceri, Laura | Gelfo, Francesca | Foti, Francesca | Laricchiuta, Daniela | Scattoni, Maria Luisa | Calamandrei, Gemma | Petrosini, Laura

Article Type: Research Article

Abstract: The “cholinergic hypothesis” of dementia posits that the progressive loss of basal forebrain cholinergic neurons and the consequent decrease of acetylcholine levels in the deafferented projection sites are correlated with degree of cognitive decline in dementia. It has also been proposed that early dysfunction of the basal forebrain (BF) cholinergic system may be a risk factor for subsequent cognitive decline and possibly dementia. To characterize how age when BF cholinergic system is lesioned affects behavioral performances and morphology of neocortical neurons, seven-day-old rats were bilaterally i.c.v. injected with 192 IgG-saporin. In adulthood, these animals were subjected to spatial and associative …tests. Subsequently, the morphology of parietal pyramidal neurons was assessed. The same behavioral and morphological evaluations were made in 80-day-old rats tested three weeks after bilateral i.c.v. injections of 192 IgG-saporin. The behavioral consequences of both cholinergic depletions were markedly similar. While both groups of lesioned animals exhibited very subtle deficits in the Morris water maze, they were significantly impaired in spatial discrimination in the open field and the radial maze. Paralleling behavioral data, the results of the morphological analysis revealed comparable increases in number and density of spines in apical and basal dendrites in layer-III parietal pyramidal neurons following both neonatal and adult cholinergic depletions. The present results demonstrate that the consequences of abnormal maturation of the cholinergic system are not substantially different from those evoked by cholinergic dysfunction in adulthood and provide a developmental psychobiological perspective of the neuronal foundations of the impaired cognitive functions. Show more

Keywords: Age effect, Alzheimer's disease, cholinergic lesion, 192 IgG-saporin, neuronal morphology, pyramidal neurons, rat, spatial function

DOI: 10.3233/JAD-2010-1355

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 207-227, 2010

Authors: García-Matas, Silvia | de Vera, Núria | Aznar, Arantxa Ortega | Marimon, Josep M. | Adell, Albert | Planas, Anna M. | Cristòfol, Rosa | Sanfeliu, Coral

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease. Age is the main risk factor for sporadic AD, which is the most prevalent type. Amyloid-β peptide (Aβ) neurotoxicity is the proposed first step in a cascade of deleterious events leading to AD pathology and dementia. Glial cells play an important role in these changes. Astrocytes provide vital support to neurons and modulate functional synapses. Therefore, the toxic effects of Aβ on astrocytes might promote neurodegenerative changes that lead to AD. Aging reduces astrocyte antioxidant defenses and induces oxidative stress. We studied the effects of Aβ42 on cultures of human …astrocytes in the presence or absence of the following pro-oxidant agents: buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, and FeSO4 , which liberates redox active iron. Pro-oxidant conditions potentiated Aβ toxicity, as shown by the generation of free radicals, inflammatory changes, and apoptosis. Similar treatments were assessed in rats in vivo. A combination of Aβ40 and Aβ42 or Aβ42 alone was infused intracerebroventricularly for 4 weeks. Other animal groups were also infused with BSO and FeSO4 . A long-term analysis that ended 4 months later showed greater cognitive impairment in the Morris water maze task, which was induced by Aβ plus pro-oxidant agent treatments. Pro-oxidant agents also potentiated brain tissue pathology. This was demonstrated in histological studies that showed highly increased astrocyte reactivity in AD-vulnerable areas, Aβ deposits, and oxidative damage of AD-sensitive hippocampal neurons. To increase our understanding of AD, experimental models should be used that mimic age-related brain changes, in which age-related oxidative stress potentiates the effects of Aβ. Show more

Keywords: Amyloid-β peptide, human astrocyte cultures, inflammation, iron, oxidative stress, rat model of Alzheimer's disease

DOI: 10.3233/JAD-2010-1365

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 229-245, 2010

Authors: Boada, Mercè | Antúnez, Carmen | López-Arrieta, Jesús | Galán, José Jorge | Morón, Francisco J. | Hernández, Isabel | Marín, Juan | Martínez-Lage, Pablo | Alegret, Montserrat | Carrasco, Jose M. | Moreno, Concha | Real, Luis M. | González-Pérez, Antonio | Tárraga, Lluís | Ruiz, Agustín

Article Type: Research Article

Abstract: CALHM1 gene coding non-synonymous SNP P86L (rs2986017) was reported to increase the risk of Alzheimer's disease (AD) in a recent study. We have investigated this genetic variant in 2470 individuals from Spain to conduct an independent replication study of the proposed SNP marker. By applying a recessive model, we observed weak evidence of an association between P86L mutation and late-onset AD (LOAD) susceptibility in our case-control study (OR = 1.38 C.I. = [1.01–1.89]). Meta-analysis of available studies also supports a recessive model for CALHM1 P86L variant and provides evidence of between study heterogeneity. Importantly, we found that adjusted mean age …at AD onset in P86L homozygous LOAD patients was significantly earlier that in the rest of patients (77.01 ± 6.1 for P86L homozygous carriers versus 79.0 ± 6.0 for the rest of patients, p = 0.002). We concluded that the CALMH1 gene may contribute to AD risk in our study population. The observed genetic model (recessive) and the estimated magnitude of the effect both imply that virtually all studies performed to date were markedly underpowered to detect this effect and underscore the importance of follow up, replication, and meta-analyses of promising genetic signals. Show more

Keywords: Alzheimer's disease, association, CALHM1, genotype, meta-analysis, molecular genetics, polymorphism

DOI: 10.3233/JAD-2010-1357

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 247-251, 2010

Authors: Mulder, Sandra D. | van der Flier, Wiesje M. | Verheijen, Jan H. | Mulder, Cees | Scheltens, Philip | Blankenstein, Marinus A. | Hack, C. Erik | Veerhuis, Robert

Article Type: Research Article

Abstract: Several studies have shown that reduced amyloid-β 1–42 (Aβ42 ) and increased tau levels in cerebrospinal fluid (CSF) reflect increased Alzheimer's disease (AD) pathology in the brain. β-site APP cleaving enzyme (BACE1) is thought to be the major β-secretase involved in Aβ production in the brain, and therefore we investigated the relation between BACE1 activity and CSF markers Aβ40 , Aβ42 , total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau) in CSF of control (n = 12), mild cognitive impairment (n = 18), and AD (n = 17) subjects. Patients were classified according to their Aβ42 , t-tau, …and p-tau CSF biomarker levels, with either an AD-like biomarker profile (two or three biomarkers abnormal: Aβ42 495 pg/ml in combination with t-tau > 356 pg/ml, and/or p-tau > 54 pg/ml) or a normal biomarker profile (⩽ one biomarker abnormal). This resulted in 19 subjects with an AD-like biomarker profile (66 ± 6 years, 53% female, and Mini-Mental Status Examination (MMSE) score: 23 ± 5) and 28 subjects with a normal biomarker profile (62 ± 11 years, 43% female, and MMSE score: 27 ± 4). Subjects with an AD-like biomarker profile had higher CSF BACE1 activity levels, compared to patients with a normal biomarker profile (20 pg/ml and 16 pg/ml respectively; p = 0.01), when controlled for age and gender. In the whole sample, BACE1 activity correlated with CSF levels of Aβ40 , t-tau, and p-tau (r = 0.38, r = 0.63, and r = 0.65; all p < 0.05), but not with Aβ42 . These data suggest that increased BACE1 activity in CSF relates to AD pathology in the brain. Show more

Keywords: Aβ40, Aβ42, Alzheimer's disease, BACE1 activity, CSF biomarker profile, p-tau, t-tau

DOI: 10.3233/JAD-2010-1367

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 253-260, 2010

Authors: Jin, Haifeng | Sanjo, Nobuo | Uchihara, Toshiki | Watabe, Kazuhiko | George-Hyslop, Peter St. | Fraser, Paul E. | Mizusawa, Hidehiro

Article Type: Research Article

Abstract: Presenilin-1 (PSEN1) is a primary component of the γ-secretase complex, and total levels of its holoprotein and endoproteolytic fragments are tightly regulated. We examined the effects of several types of endoplasmic reticulum (ER) stress on quantitative changes in the levels of PSEN1 mRNA, holoprotein, and fragments. The ER stress-inducing chemical compounds tunicamycin, brefeldin-A, thapsigargin, and staurosporine were added to the culture media of various human cell lines. Tunicamycin treatment caused a doubling of PSEN1 holoprotein production in HEK293 cells and an increase in holoprotein production to approximately 180% in GOTO human neuroblastoma and KNS-42 human glioma cell lines, without changing …the amounts of PSEN1 N- or C-terminal fragments. The elevated holoprotein level in HEK293 cells was accompanied by an increase in PSEN1 mRNA expression. HEK293 cells that stably overexpressed PSEN1 holoprotein showed increased resistance to ER stress induced by tunicamycin, but they did not show resistance to ER stress caused by thapsigargin, a specific inhibitor of sarco ER calcium-ATPase (SERCA). In wild-type HEK293 cells under ER stress induced by tunicamycin, an increased amount of SERCA interacted with PSEN1 holoprotein. PSEN1 production varied among cell types and circumstances. The results suggested that the holoprotein forms a complex with the SERCA channel and participates in the regulation of intracellular calcium homeostasis. These findings provide support for the calcium hypothesis of Alzheimer's disease. Show more

Keywords: Endoplasmic reticulum stress, presenilin, PS1, PSEN1, PS2, PSEN2, sarco ER calcium-ATPase, SERCA, tunicamycin

DOI: 10.3233/JAD-2010-1360

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 261-273, 2010

Authors: Raychaudhuri, Mithu | Mukhopadhyay, Debashis

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is processed by various proteases located along the endosomal lysosomal pathway and any alteration in its trafficking would be important in the pathogenesis of Alzheimer's disease (AD). Our current study is based on the clinical evidence that an AβPP intracellular domain (AICD) “adaptor” protein, growth factor receptor protein binding protein 2 (Grb2), gets concentrated in neuronal cell bodies in AD patients. Here we show that both endogenous and exogenously transfected Grb2 interact with AβPP in Neuro 2A cells. Endogenous Grb2 partially co-localizes to late endosomal compartments along with AβPP and AICD. Increase in the concentration …of Grb2 confines it in enlarged late endosomes leading to more sequestration of AβPP and AICD within these compartments. This confinement of AβPP due to Grb2 overexpression affects its turnover by inhibiting its release via exosomal vesicles. As a consequence, the level of intracellular AβPP and AICD increases. The effect of Grb2 overexpression has been verified by knocking down Grb2 as well as by overexpressing Grb2 in Grb2 knocked down cells. Having established the Grb2-mediated trafficking of AICD and its impairment, the significance of its consequence has now become apparent in the downstream events of AD pathogenesis. Show more

Keywords: Amyloid-β protein precursor (AβPP), AβPP intracellular domain (AICD), endosomal-lysosomal pathway, exosome, Grb2

DOI: 10.3233/JAD-2010-1371

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 275-292, 2010

Authors: Qiu, Chengxuan | Xu, Weili | Winblad, Bengt | Fratiglioni, Laura

Article Type: Research Article

Abstract: Numerous studies have linked individual vascular factors to dementia including Alzheimer's disease (AD). We investigated different vascular risk profiles in relation to dementia and AD among very old people. A standardized follow-up procedure was applied three times to a dementia-free cohort (n = 1270, age ⩾ 75) over a nine-year period to detect dementia and AD cases using the DSM-III-R criteria. We examined two vascular risk profiles, which were scored by counting the number of corresponding vascular factors: 1) atherosclerotic profile included systolic pressure ⩾ 160 mmHg, diabetes/prediabetes, and stroke; and 2) cerebral hypoperfusion profile constituted diastolic pressure < 70 …mmHg, pulse pressure < 70 mmHg, and heart failure. Data were analyzed with Cox proportional-hazards models controlling for major potential confounders. During the 6406 person-years of follow-up, 428 subjects developed dementia, including 328 AD cases. All components of vascular profiles were significantly or marginally associated with increased dementia risk. The risk of dementias was increased with increasing score of both risk profiles (p for trend ⩽ 0.001); subjects with a score ⩾ 2 in either profile had an approximately twofold-increased risk for dementia and AD. These data suggest that aggregation of atherosclerotic- and hypoperfusion-related vascular factors increases the risk of dementia in very old people. Severe cerebral atherosclerosis and insufficient perfusion are involved in the development of dementia including AD. Show more

Keywords: Alzheimer's disease, atherosclerosis, cerebral blood flow, cohort study, dementia, vascular factors

DOI: 10.3233/JAD-2010-1361

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 293-300, 2010

Authors: Cummings, Jeffrey | Emre, Murat | Aarsland, Dag | Tekin, Sibel | Dronamraju, Nalina | Lane, Roger

Article Type: Research Article

Abstract: Hallucinations in Alzheimer's disease (AD) may indicate greater cortical cholinergic deficits. Rivastigmine has shown larger treatment benefits versus placebo in dementia with Lewy bodies and Parkinson's disease dementia patients with hallucinations. In this retrospective, hypothesis-generating analysis, we investigated whether hallucinations in AD were associated with greater treatment benefits with rivastigmine. Data were pooled from two randomized, double-blind, 6-month, mild-to-moderate AD trials comparing rivastigmine with placebo. Co-primary efficacy parameters were the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). Efficacy data were analyzed for two sub-populations: those with and those without hallucinations at …baseline. Of 927 patients, 194 (21%) reported hallucinations at baseline. Hallucinators tended to have greater decline on placebo on all outcome measures. On the ADAS-cog, mean rivastigmine − placebo differences of 3.7 points in hallucinators and 2.2 points in non-hallucinators were reported at 6 months (both p < 0.001). In hallucinators, a significant rivastigmine − placebo difference of −1.0 points (a beneficial effect) was seen on the CIBIC-plus at 6 months (p < 0.001). Non-hallucinators showed a smaller significant treatment difference of −0.3 points (p < 0.05). Interaction testing suggested that differences in treatment effects were significant between hallucinators and non-hallucinators. Hallucinations predicted greater treatment responses to oral rivastigmine. Show more

Keywords: Alzheimer's disease, cholinesterase inhibitor, hallucinations, rivastigmine

DOI: 10.3233/JAD-2010-1362

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 301-311, 2010

Authors: Loskutova, Natalia | Honea, Robyn A. | Brooks, William M. | Burns, Jeffrey M.

Article Type: Research Article

Abstract: Accelerated bone loss is associated with Alzheimer's disease (AD). Although the central nervous system plays a direct role in regulating bone mass, primarily through the actions of the hypothalamus, there is little work investigating the possible role of neurodegeneration in bone loss. In this cross-sectional study, we examined the association between bone mineral density (BMD) and neuroimaging markers of neurodegeneration (i.e., global and regional measures of brain volume) in early AD and non-demented aging. Fifty-five non-demented and 63 early AD participants underwent standard neurological and neuropsychological assessment, structural MRI scanning, and dual energy x-ray absorptiometry. In early AD, voxel-based morphometry …analyses demonstrated that low BMD was associated with low volume in limbic grey matter (GM) including the hypothalamus, cingulate, and parahippocampal gyri and in the left superior temporal gyrus and left inferior parietal cortex. No relationship between BMD and regional GM volume was found in non-demented controls. The hypothesis-driven region of interest analysis further isolating the hypothalamus demonstrated a positive relationship between BMD and hypothalamic volume after controlling for age and gender in the early AD group but not in non-demented controls. These results demonstrate that lower BMD is associated with lower hypothalamic volume in early AD, suggesting that central mechanisms of bone remodeling may be disrupted by neurodegeneration. Show more

Keywords: Alzheimer's disease, bone density, hypothalamus, voxel-based morphometry

DOI: 10.3233/JAD-2010-1364

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 313-322, 2010

Authors: Zheng, Wei | Wang, Tao | Yu, Dan | Feng, Wan-Yu | Nie, Ying-Xue | Stoltenberg, Meredin | Danscher, Gorm | Wang, Zhan-You

Article Type: Research Article

Abstract: The presence of senile plaques containing abundant amyloid-β (Aβ) peptide is one of the major pathological hallmarks of Alzheimer's disease (AD). Recent studies support the notion that overexpression of zinc transporters (ZnT) is involved in zinc metabolic disturbances and Aβ aggregation in AD brains. Here we present data showing an elevated expression of zinc transporter 3 (ZnT3) protein, revealed by immunoblotting assay, in the cerebellum of the amyloid-β protein precursor (AβPP)/presenilin 1 (PS1) transgenic mouse. Confocal microscopic and autometallographic results showed that ZnT3 immunofluorescence and zinc ions were predominantly located in the amyloid plaques. ZnT3 protein was abundantly distributed throughout …the plaques, whereas zinc ions were mainly located in the peripheral parts of rosette-shaped plaques with a lightly stained center. Collectively, our results suggest that ZnT3 protein is involved in the Aβ aggregation in the cerebellum of the AβPP/PS1 mouse. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, cerebellum, ionic zinc, SLC30A3

DOI: 10.3233/JAD-2010-1363

Citation: Journal of Alzheimer's Disease, vol. 20, no. 1, pp. 323-331, 2010