Journal of Alzheimer's Disease - Volume 29, issue 4

Authors: Kindy, Mark S. | Yu, Jin | Zhu, Hong | El-Amouri, Salim S. | Hook, Vivian | Hook, Gregory R.

Article Type: Research Article

Abstract: Therapeutic agents that improve the memory loss of Alzheimer's disease (AD) may eventually be developed if drug targets are identified that improve memory deficits in appropriate AD animal models. One such target is β-secretase which, in most AD patients, cleaves the wild-type (WT) β-secretase site sequence of the amyloid-β protein precursor (AβPP) to produce neurotoxic amyloid-β (Aβ). Thus, an animal model representing most AD patients for evaluating β-secretase effects on memory deficits is one that expresses human AβPP containing the WT β-secretase site sequence. BACE1 and cathepsin B (CatB) proteases have β-secretase activity, but gene knockout studies have not yet …validated that the absence of these proteases improves memory deficits in such an animal model. This study assessed the effects of deleting these protease genes on memory deficits in the AD mouse model expressing human AβPP containing the WT β-secretase site sequence and the London γ-secretase site (AβPPWT/Lon mice). Knockout of the CatB gene in the AβPPWT/Lon mice improved memory deficits and altered the pattern of Aβ-related biomarkers in a manner consistent with CatB having WT β-secretase activity. But deletion of the BACE1 gene had no effect on these parameters in the AβPPWT/Lon mice. These data are the first to show that knockout of a putative β-secretase gene results in improved memory in an AD animal model expressing the WT β-secretase site sequence of AβPP, present in the majority of AD patients. CatB may be an effective drug target for improving memory deficits in most AD patients. Show more

Keywords: Amyoid-β, amyoid-β protein precursor, cathepsin B, gene knockout, protease

DOI: 10.3233/JAD-2012-111604

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 827-840, 2012

Authors: León-Espinosa, Gonzalo | DeFelipe, Javier | Muñoz, Alberto

Article Type: Research Article

Abstract: The output of cortical pyramidal cells reflects the balance between excitatory inputs of cortical and subcortical origin, and inhibitory inputs from distinct populations of cortical GABAergic interneurons, each of which selectively innervate different domains of neuronal pyramidal cells (i.e., dendrites, soma and axon initial segment [AIS]). In Alzheimer's disease (AD), the presence of amyloid-β (Aβ) plaques alters the synaptic input to pyramidal cells in a number of ways. However, the effects of Aβ plaques on the AIS have still not been investigated to date. This neuronal domain is involved in input integration, as well as action potential initiation and propagation, …and it exhibits Ca2+ - and activity-dependent structural plasticity. The AIS is innervated by GABAergic axon terminals from chandelier cells, which are thought to exert a strong influence on pyramidal cell output. In the AβPP/PS1 transgenic mouse model of AD, we have investigated the effects of Aβ plaques on the morphological and neurochemical features of the AIS, including the cisternal organelle, using immunocytochemistry and confocal microscopy, as well as studying the innervation of the AIS by chandelier cell axon terminals. There is a strong reduction in GABAergic terminals that appose AIS membrane surfaces that are in contact with Aβ plaques, indicating altered inhibitory synapsis at the AIS. Thus, despite a lack of gross structural alterations in the AIS, this decrease in GABAergic innervation may deregulate AIS activity and contribute to the hyperactivity of neurons in contact with Aβ plaques. Show more

Keywords: Alzheimer's disease, ankyrin G, chandelier cells, cisternal organelle, synaptopodin

DOI: 10.3233/JAD-2012-112036

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 841-852, 2012

Authors: Palmer, Jennifer C. | Barker, Rachel | Kehoe, Patrick G. | Love, Seth

Article Type: Research Article

Abstract: Vascular dysfunction and lowered cerebral blood flow are thought to contribute to the development and progression of Alzheimer's disease (AD). Endothelin-1 (ET-1) is a potent vasoconstrictor, the production of which is mainly catalyzed by endothelin-converting enzymes (ECEs). We previously showed that ECE-2 is upregulated by amyloid-β (Aβ), and its expression elevated in AD postmortem brain tissue. We have now investigated whether there is a concomitant increase in ET-1. We studied temporal cortex from 20 cases of sporadic AD and 20 matched controls. The cellular distribution of ET-1 was assessed immunohistochemically in paraffin sections. PreproET-1 (EDN1) mRNA and ET-1 protein were …measured in homogenates of superior temporal cortex by real-time PCR and sandwich ELISA respectively. Cultured SH-SY5Y human neuroblastoma cells were incubated with 10 μM oligomeric Aβ42 for 24 h, and ET-1 protein level was measured in cell culture supernatants by sandwich ELISA. Antibody to ET-1 labeled neurons throughout the temporal cortex, and the walls of some cerebral blood vessels. ET-1 mRNA measured in the temporal neocortex was significantly elevated in AD when normalized for expression of GAPDH (p = 0.0256) or the neuronal marker neuron-specific enolase (NSE, p = 0.0001). ET-1 protein was also significantly higher in AD than in control tissue, when adjusted for neuronal content by measurement of NSE (p = 0.0275). ET-1 protein in SH-SY5Y cell supernatant rose 1.7-fold after exposure to 10 μM oligomeric Aβ (p = 0.024). These findings provide evidence of overactivity of the endothelin system in AD, further supporting the suggestion that endothelin receptor antagonists may be of value for the treatment of this disease. Show more

Keywords: Alzheimer's disease, amyloid-β, cerebral ischemia, cerebrovascular disorders, cerebrovascular circulation, endothelin-1, vasoconstriction

DOI: 10.3233/JAD-2012-111760

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 853-861, 2012

Authors: Beyer, Nancy | Coulson, David T.R. | Heggarty, Shirley | Ravid, Rivka | Hellemans, Jan | Irvine, G. Brent | Johnston, Janet A.

Article Type: Research Article

Abstract: Zinc (Zn2+ ) is concentrated into pre-synaptic vesicles and co-released with neurotransmitter at some synapses. Zn2+ can accelerate assembly of the amyloid-β peptides (Aβ) and tau protein central to the neuropathological changes found in Alzheimer's disease (AD). Altered protein levels of the membrane Zn2+ transporters ZnT1, ZnT4, and ZnT6 have been reported in AD postmortem brain tissue. The present study analyzed mRNA levels of five established (LIV1, ZIP1, ZnT1, ZnT4, and ZnT6) and one potential (PRNP) Zn2+ transporter in human postmortem brain tissue from Braak-staged individuals with AD and controls using quantitative real-time PCR. Four cortical regions …(middle temporal gyrus, superior occipital gyrus, superior parietal gyrus, and superior frontal gyrus) and cerebellum were examined. PRNP mRNA levels were decreased by ∼30% in all four cortical regions examined in AD patients, but unchanged in the cerebellum. In contrast, some increases in mRNA levels of the other more established Zn2+ transporters (LIV1, ZIP1, ZnT1, ZnT6) were found in AD cortex. The ratios of the mRNA levels of LIV1, ZIP1, ZnT1, ZnT4, and ZnT6/mRNA level of neuron specific enolase increased significantly as the disease progressed and Braak stage increased. Significant correlations were also identified between mRNA levels of several of the Zn2+ transporters investigated. These expression changes could either reflect or cause the altered cortical Zn2+ distribution in AD, potentially increasing the likelihood of interactions between Zn2+ and Aβ or tau protein. Show more

Keywords: LIV1 protein, neurodegenerative diseases, prion protein, reverse transcriptase polymerase chain reaction, zinc, ZIP1 protein, ZnT1 protein, ZnT4 protein, ZnT6 protein

DOI: 10.3233/JAD-2012-112105

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 863-873, 2012

Authors: Mold, Matthew | Shrive, Annette K. | Exley, Christopher

Article Type: Research Article

Abstract: The mechanism whereby an under-saturated solution of amyloid-β (Aβ)42 precipitates as β sheets in vivo in Alzheimer's disease remains to be elucidated. Herein we present in vitro evidence that serum amyloid P component may mediate this process through its acceleration of amyloid formation from an under-saturated solution of Aβ42 and subsequently its stabilization of the amyloid fibrils formed over physiologically significant timeframes. Our observations support serum amyloid P component as a therapeutic target in Alzheimer's disease.

Keywords: Aluminum, amyloid-β, amyloid fibrils, copper, serum amyloid P component, transmission electron microscopy

DOI: 10.3233/JAD-2012-120076

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 875-881, 2012

Authors: Borroni, Barbara | Grassi, Mario | Premi, Enrico | Alberici, Antonella | Cosseddu, Maura | Cancelli, Vanessa | Caobelli, Federico | Paghera, Barbara | Padovani, Alessandro

Article Type: Research Article

Abstract: Prediction of survival in frontotemporal lobar degeneration (FTLD) is guesswork. The aim of the present study was to evaluate whether SPECT scan may be useful to predict prognosis of long term survival in FTLD patients. A cohort of 125 patients with FTLD who underwent brain SPECT scan at the time of enrollment and who were further followed up for at least one year were considered. In each subject, volume of interests (VOIs) covering frontotemporal and parietal regions, bilaterally, were drawn. Principal component analysis (PCA) was applied on VOIs, and a Cox regression model was carried out to find out best …predictors of survival. A two-pattern PCA solution was chosen, explaining more than 70% of variance, and “frontal” PC1 and “temporal” PC2 components were identified. The frontal PC1 was associated with higher rate of faster progression (HR = 2.06, 95% CI = 1.23–3.44, p = 0.006 for univariate model, and HR = 1.85, 95% CI = 1.04–3.28, p = 0.03 for multivariate model). In particular, right orbitofrontal cortex showed the higher loadings in PC1; the worse the scores of this region the shorter the survival was reported. We suggest that SPECT imaging, beyond a helpful tool in diagnostic assessment, may be an easily and accessible marker of disease outcome in FTLD. Further studies considering structural neuroimaging are warranted. Show more

Keywords: Frontotemporal lobar degeneration, neuroimaging, prognosis, progression, SPECT

DOI: 10.3233/JAD-2012-112078

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 883-890, 2012

Authors: Le Duff, Franck | Develay, Aude Emmanuelle | Quetel, Julien | Lafay, Pierre | Schück, Stéphane | Pradier, Christian | Robert, Philippe | the participating centers

Article Type: Research Article

Abstract: In France, one of the aims of the current national Alzheimer's disease plan is to collect data from all memory centers (memory units, memory resource and research centers, independent neurologists) throughout the country. Here we describe the French Alzheimer Information System and present a ‘snapshot’ of the data collected throughout the country during the first year of operation. We analyzed all data transmitted by memory centers between January 2010 and December 2010. Each participating center is required to transmit information on patients to the French National Alzheimer dataBank (BNA). This involves completing a computer file containing 31 variables corresponding to …a limited data set on AD (CIMA: Corpus minimum d'information Alzheimer). In 2010, the BNA received data from 320 memory centers relating to 199,113 consultations involving 118,776 patients. An analysis of the data shows that the initial MMSE (Mini Mental State Examination) mean score for patients in France was 16.8 points for Alzheimer's disease, 25.7 points for mild cognitive impairment, and 18.8 points for ‘related disorders related disorders. The BNA will provide longitudinal data that can be used to assess the needs of individual local health areas and size specialized care provision in each regional health scheme. By contributing to the BNA, the memory centers enhance their clinical activity and help to advance knowledge in epidemiology and medical research in the important field of Alzheimer's disease and related dementias. Show more

Keywords: Alzheimer's disease, dementia, medical practice, public health

DOI: 10.3233/JAD-2012-111943

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 891-902, 2012

Authors: Benisty, Sarah | Reyes, Sonia | Godin, Ophelia | Hervé, Dominique | Zieren, Nikola | Jouvent, Eric | Zhu, Yicheng | During, Marco | Dichgans, Martin | Chabriat, Hugues

Article Type: Research Article

Abstract: To better characterize the clinical spectrum related to white-matter hyperintensities (WMH) in small vessel disease, 66 patients with WMH but without any lacunar infarct were selected out of a cohort of 248 CADASIL individuals. Characteristics of these patients were compared to those of patients with lacunar infarcts. Relationships between the normalized volume of WMH (nWMH), presence of microhemorrhages, brain parenchymal fraction (BPF). and cognitive performances were assessed. The Trail Making Test (TMT) A and B times, Mattis Dementia Rating Scale (MDRS) total score, attention subscore, verbal fluency score and delayed memory recall were significantly correlated with nWMH but not with …BPF. Presence of microhemorrhages was associated with worse TMT B time and attention MDRS subscore after adjustment for WMH. All subjects had Mini-Mental Status Examination scores ≥24 and presented with no or only mild disability. These results suggest that CADASIL patients with isolated WMH can present with executive and attention deficit but not with severe disability and that additional lesions are needed to cause significant disability and/or dementia. Show more

Keywords: CADASIL, cerebral small vessel disease, cognitive impairment, dementia, MRI, white matter hyperintensities

DOI: 10.3233/JAD-2012-111784

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 903-911, 2012

Authors: Bucossi, Serena | Polimanti, Renato | Mariani, Stefania | Ventriglia, Mariacarla | Bonvicini, Cristian | Migliore, Simone | Manfellotto, Dario | Salustri, Carlo | Vernieri, Fabrizio | Rossini, Paolo M. | Squitti, Rosanna

Article Type: Research Article

Abstract: Copper homeostasis appears abnormal in Alzheimer's disease (AD) patients. The aim of this study was to assess whether loci of susceptibility for AD lie in the Wilson's disease (WD) ATP7B gene. We studied single nucleotide polymorphisms (SNPs) K832R (c.2495 A>G, rs1061472) and R952K (c. 2855 G>A, rs732774) of the WD gene in 251 AD patients and 201 healthy controls. We also evaluated their relation with apolipoprotein E (ApoE) ε4 allele frequency. R allele in K832R [adjusted Odds Ratio (OR) = 1.71 (1.12–2.60); p = 0.012] and the K allele in R952K [adjusted OR = 1.82 (1.19–2.80); p = 0.006] ATP7B …SNPs were associated with an increased risk of developing AD, as well as the haplotype R832/K952, containing the 2 risk alleles (X2 = 4.85; p = 0.028). Conversely, the K832/R952 haplotype appeared to confer protection against the disease (X2 = 7.21; p = 0.007). No difference in the frequency of the ATP7B alleles between carriers and non-carriers of the ApoE ε4 variant was revealed. The linkage disequilibrium (LD) analysis revealed an association between K832R and R952K substitutions in both AD patients (D' = 0.79) and controls (D' = 0.81). A high LD between K832R and R952K was also confirmed in all HapMap populations. Our investigation demonstrated the presence of loci of susceptibility for AD in the WD ATP7B gene, supporting a role of copper dysfunction in contributing or accelerating neurodegenerative processes leading to AD. Show more

Keywords: Alzheimer's disease, ATP7B, copper, genetic association study, genetics, Wilson's disease

DOI: 10.3233/JAD-2012-111997

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 913-919, 2012

Authors: Llorens-Martin, María | Teixeira, Cátia M. | Fuster-Matanzo, Almudena | Jurado-Arjona, Jerónimo | Borrell, Víctor | Soriano, Eduardo | Avila, Jesús | Hernández, Félix

Article Type: Research Article

Abstract: In the adult hippocampal dentate gyrus, newborn granule cells grow dendrites into the molecular layer and send axons into the CA3 region. Several molecular markers have been used to analyze production of these new neurons; however, no good markers for new axons have been described. Here we demonstrate that tau protein isoform with three microtubule binding domains (3R-Tau) is a marker of those axons following an antigen retrieval protocol. By using retrovirus-mediated GFP transduction, GFP can be detected in a period of 7–14 days after viral infection. We also provide a “proof of principle” demonstration of the power of that …labeling showing modulation of 3R-Tau positive axons under physiological conditions (exercise and aging) as well as in a FTDP-17 neurodegenerative model and Alzheimer's disease models (mice overexpressing AβPPsw, ind or GSK3β). We conclude that 3R-Tau would be an efficient marker and a valuable tool to study new axons in adult neurogenesis as well as in neurodegenerative processes. Show more

Keywords: Adult neurogenesis, dentate gyrus, subgranular zone, tau protein

DOI: 10.3233/JAD-2012-112057

Citation: Journal of Alzheimer's Disease, vol. 29, no. 4, pp. 921-930, 2012