Journal of Alzheimer's Disease - Volume 32, issue 1

Authors: Sepulveda-Falla, Diego | Glatzel, Markus | Lopera, Francisco

Article Type: Review Article

Abstract: Presenilin 1 (PS1) mutations are the most common cause of early-onset familial Alzheimer's disease (EOFAD). They show a common phenotypic profile characterized by early age of onset, severe dementia and distinct neurodegeneration. The largest population of EOFAD carries the E280A mutation in PS1 and resides in Antioquia, Colombia, currently comprising around 5,000 individuals. Carriers start showing memory impairment in the third decade of life, followed by progressive impairment of language and other cognitive processes. They reach mild cognitive impairment around 45 and dementia around 50 years of age. There is some phenotypic variability among the carriers of this single PS1 …mutation. Some patients present with epilepsy, verbal impairment, and cerebellar ataxia. Neuropathologically, PS1 E280A cases show pronounced brain atrophy, severe amyloid-β pathology, distinct hyperphosphorylated tau-related pathology, and cerebellar damage. The earliest event identified by functional magnetic imaging resonance is hyperactivation within the right anterior hippocampus around 33 years of age. This well-studied population with a clear pre-clinical profile and wide phenotypic variability in age of onset and clinical presentation is ideally suited for clinical trials and to study molecular mechanisms of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, early onset, phenotype, presenilin-1

DOI: 10.3233/JAD-2012-120907

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 1-12, 2012

Authors: Tedde, Andrea | Piaceri, Irene | Bagnoli, Silvia | Lucenteforte, Ersilia | Piacentini, Silvia | Sorbi, Sandro | Nacmias, Benedetta

Article Type: Short Communication

Abstract: Apoptosis is correlated with various forms of dementia. Death-associated protein kinase 1 (DAPK1) plays an important role in neuronal apoptosis and could influence the pathology of late-onset Alzheimer's disease (LOAD) and frontotemporal dementia (FTD). It has been reported that two common polymorphisms (rs4878104 and rs4877365) are associated with LOAD, thus we examined the genotype and allele distributions of the above polymorphisms in 681 Italian subjects, including patients with LOAD and FTD. We showed a positive association between rs4878104 and FTD, suggesting a possible implication of the DAPK1 genetic variant in the susceptibility to FTD.

Keywords: Alzheimer's disease, DAPK1, frontotemporal dementia, SNP

DOI: 10.3233/JAD-2012-120556

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 13-17, 2012

Authors: Wallon, David | Rovelet-Lecrux, Anne | Deramecourt, Vincent | Pariente, Jeremie | Auriacombe, Sophie | Le Ber, Isabelle | Schraen, Suzanna | Pasquier, Florence | Campion, Dominique | Hannequin, Didier

Article Type: Short Communication

Abstract: Hexanucleotide expansion repeats in the C9ORF72 gene are a major cause of familial and, to a lesser extent, sporadic frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and FTLD-ALS. To examine whether C9ORF72 expansions could be involved in early-onset Alzheimer's disease (EOAD), we genotyped the hexanucleotide repeat region in a large cohort of 114 EOAD patients who all had positive AD cerebrospinal fluid (CSF) biomarkers. We found hexanucleotide expansion repeats of the C9ORF72 gene in 3 out of 114 patients (2.6%). We raise several hypotheses to explain our results and discuss the current status of AD CSF biomarkers in the …dementia diagnostic algorithm. Show more

Keywords: Alzheimer's disease, C9ORF72, cerebrospinal fluid biomarkers, dementia/diagnosis, frontotemporal lobar degeneration

DOI: 10.3233/JAD-2012-120877

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 19-22, 2012

Authors: Royall, Donald R. | Palmer, Raymond F.

Article Type: Research Article

Abstract: The temporal growth of Alzheimer's disease (AD) neuropathology cannot be easily determined because autopsy data are available only after death. We combined autopsy data from 471 participants in the Honolulu-Asia Aging Study (HAAS) into latent factor measures of neurofibrillary tangle and neuritic plaque counts. These were associated with intercept and slope parameters from a latent growth curve (LGC) model of 9-year change in cognitive test performance in 3244 autopsied and non-autopsied HAAS participants. Change in cognition fully mediated the association between baseline cognitive performance and AD lesions counts. The mediation effect of cognitive change on both AD lesion models effectively …dates them within the period of cognitive surveillance. Additional analyses could lead to an improved understanding of lesion propagation in AD. Show more

Keywords: Alzheimer's disease, longitudinal, neuropathology, old age

DOI: 10.3233/JAD-2012-120430

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 23-32, 2012

Authors: Waragai, Masaaki | Yoshida, Madoka | Mizoi, Mutsumi | Saiki, Ryotaro | Kashiwagi, Keiko | Takagi, Kiyoshi | Arai, Hiroyuki | Tashiro, Jun | Hashimoto, Makoto | Iwai, Naomichi | Uemura, Kenichi | Igarashi, Kazuei

Article Type: Research Article

Abstract: The objective of this study was to determine whether plasma levels of acrolein, a compound that causes cell damage, and amyloid-β (Aβ) are useful biochemical markers for Alzheimer's disease (AD). The study included 221 elderly subjects divided into 101 non-demented [33 healthy control and 68 non-demented subjects with white matter hyperintensity (nd-WMH)], 50 mild cognitive impairment (MCI), and 70 AD. Increases in both protein-conjugated acrolein (PC-Acro) and Aβ40/42 ratio were observed in MCI and AD patients compared with values in control subjects. When the combined measurements of PC-Acro and Aβ40/42 ratio were evaluated using the median value of …the relative risk value for dementia, they were in the order AD (0.98) ≥ MCI (0.97) > nd-WMH (0.83) > control (0.35). The results indicate that measurements of PC-Acro and Aβ40/42 ratio not only detect MCI and AD patients but also nd-WMH subjects. Furthermore, both PC-Acro and Aβ40/42 ratio in plasma for 120 MCI and AD patients were significantly higher than those for 101 control and nd-WMH subjects, indicating that both values become useful biochemical markers for MCI and AD subjects. Show more

Keywords: Alzheimer's disease, amyloid-β, magnetic resonance imaging, plasma biomarker, protein-conjugated acrolein, white matter hyperintensity

DOI: 10.3233/JAD-2012-120253

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 33-41, 2012

Authors: Barua, Neil U. | Miners, J. Scott | Bienemann, Alison S. | Wyatt, Marcella J. | Welser, Katharina | Tabor, Alethea B. | Hailes, Helen C. | Love, Seth | Gill, Steven S.

Article Type: Research Article

Abstract: Enzymatic degradation contributes to the control of intracerebral amyloid-β (Aβ) peptide levels. Previous studies have demonstrated the therapeutic potential of viral vector-mediated neprilysin (NEP) gene therapy in mouse models of Alzheimer's disease (AD). However, clinical translation of NEP gene therapy is limited by ethical and practical considerations. In this study we have assessed the potential of convection-enhanced delivery (CED) as a means of elevating intracerebral NEP level and activity and degrading endogenous Aβ. We analyzed the interstitial and perivascular distribution of NEP following CED into rat striatum. We measured NEP protein level, clearance, activity, and toxicity by ELISA for NEP …and synaptophysin, NEP-specific activity assay, and immunohistochemistry for NEP, NeuN, glial fibrillary acidic protein and Iba1. We subsequently performed CED of NEP in normal aged rats and measured endogenous Aβ by ELISA. CED resulted in widespread distribution of NEP, and a 20-fold elevation of NEP protein level with preservation of enzyme activity and without evidence of toxicity. CED in normal, aged rats resulted in a significant reduction in endogenous Aβ40 (p = 0.04), despite rapid NEP clearance from the brain (half-life ~3 h). CED of NEP has therapeutic potential as a dynamically controllable Aβ40 -degrading therapeutic strategy for AD. Further studies are required to determine the longer term effects on Aβ (including Aβ42 ) and on cognitive function. Show more

Keywords: Alzheimer's disease, amyloid-β, convection-enhanced delivery, neprilysin, therapy

DOI: 10.3233/JAD-2012-120658

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 43-56, 2012

Authors: Solano, Rosa M. | Casarejos, Maria J. | Gómez, Ana | Perucho, Juan | de Yébenes, Justo García | Mena, Maria A.

Article Type: Research Article

Abstract: Dementia occurs often in late stages of Parkinson's disease (PD) but its cause is unknown. Likewise there is little information about the interaction between proteins that produce PD and those implicated in Alzheimer's disease (AD). Here we have investigated the interactions between parkin protein and the amyloid-β (Aβ)1-42 peptide. We examined the effects of oligomeric Aβ1-42 peptide on the survival, differentiation, and signaling pathways in cortical cultures from wild type (WT) and parkin null (PK-KO) mice. We discovered that PK-KO cells were more resistant than WT to Aβ1-42 . This peptide induced neuronal cell death, astrogliosis, microglial proliferation, …and increased total and hyperphosphorylated tau and levels of chaperones HSP-70 and CHIP in WT, but not in Aβ-treated PK-KO cultures. Aβ1-42 decreased proteasome activities in WT and PK-KO cultures, but the ubiquitination of proteins only increased in WT cultures. Aβ1-42 induced a short activation of ERK1/2 and AKT signaling pathways, implicated in cell survival, in PK-KO-treated cells, and a shift in the autophagy marker LC3-II/LC3-I ratio. In addition, the percentage of cells immunoreactive to both HSC70 and LAMP-2A increased in PK-KO cultures versus WT and furthermore in PK-KO cultures treated with Aβ1-42 . Pre-treatment with inhibitors of glutathione synthesis or autophagy reverted the resistance to Aβ1-42 of the PK-KO cultures. In conclusion, the loss of parkin protein triggers the compensatory mechanisms of cell protection against Aβ1-42 . Parkin suppression, therefore, is not a risk factor for dementia of AD type. Show more

Keywords: Alzheimer's disease, apoptosis, autophagy-lysosomal pathway, chaperones, cortical neuron/glial cultures, glutathione, Park 2 gene, ubiquitin proteasome system

DOI: 10.3233/JAD-2012-120406

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 57-76, 2012

Authors: Wang, Xichao | Chen, Qun | Xing, Da

Article Type: Research Article

Abstract: Increasing evidence supports that amyloid plaques, comprised of amyloid-β (Aβ), are a key feature of Alzheimer's disease (AD). But the mechanism of Aβ in AD is not yet fully understood. Previous studies have demonstrated that in Aβ-induced apoptosis of nerve cells, differentiated rat pheochromocytoma (PC12) cells, and microglia, nucleus factor kappa B (NF-κB) is activated. Meanwhile, focal adhesion kinase (FAK) is also activated. However, the relationship between NF-κB and FAK remains unclear. Using differentiated PC12 cells, we investigated this relationship in Aβ25-35 -induced apoptosis. The results showed that FAK phosphorylation increased at 6–9 hours after Aβ treatment, slightly shorter than …the activation of NF-κB (6–12 hours). In this process, both extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38MAPK) phosphorylation levels were increased. After FAK expression was inhibited by its siRNA, the activities of ERK1/2, p38MAPK, and NF-κB were all suppressed. When ERK1/2 and p38MAPK expressions were inhibited by their siRNAs respectively, NF-κB activity was also suppressed. But FAK phosphorylation was not affected. When NF-κB expression was inhibited, all of the phosphorylation levels of FAK, ERK1/2, and p38MAPK were not affected. These phenomena indicated that FAK is upstream of ERK1/2, p38MAPK, and NF-κB, and meanwhile both of ERK1/2 and p38MAPK are upstream of NF-κB. Co-immunoprecipitation results demonstrated that it is ERK1/2, but not p38MAPK, which directly interacts with IκB kinase. Taken together, our results suggest that FAK activates NF-κB via ERK1/2 and p38MAPK pathways in Aβ25-35 -induced apoptosis of differentiated PC12 cells. Show more

Keywords: Amyloid-β, ERK1/2, focal adhesion kinase, NF-κB, p38MAPK, PC12

DOI: 10.3233/JAD-2012-120526

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 77-94, 2012

Authors: Maetzler, Walter | Langkamp, Markus | Lerche, Stefanie | Godau, Jana | Brockmann, Kathrin | Gaenslen, Alexandra | Huber, Heiko | Wurster, Isabel | Niebler, Raphael | Eschweiler, Gerhard W. | Berg, Daniela

Article Type: Research Article

Abstract: Reduced levels of naturally occurring autoantibodies against amyloid-β (Aβ) have been described in Alzheimer's disease (AD). Lifetime depression doubles the risk of AD, thus these autoantibodies may also be reduced in this group. We measured serum IgG autoantibody titers against Aβ1-42 , S100b and α-synuclein in 214 individuals with depression and 419 controls. Titers against Aβ1-42 were lower in individuals with lifetime depression (5544.6 ± 389.3) compared to controls (7208.7 ± 482.4; p = 0.048). Titers against S100b and α-synuclein were comparable between the cohorts. These data suggest an AD-like impairment of the humoral immune response in a relevant …proportion of individuals with depression. Show more

Keywords: Alzheimer's disease, autoimmune disease, depression, risk factor

DOI: 10.3233/JAD-2012-120625

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 95-100, 2012

Authors: Little, Deborah M. | Foxely, Sean | Lazarov, Orly

Article Type: Research Article

Abstract: We have shown that experience of transgenic mice harboring familial Alzheimer's disease (FAD)-linked AβPPswe/PS1ΔE9 in an enriched environment enhances hippocampal neurogenesis and synaptic plasticity and attenuates neuropathology. Nevertheless, the neuronal pathways activated following environmental enrichment underlying this effect are unknown. Using resting-state functional magnetic resonance imaging, we present preliminary evidence to show that transgenic mice, which had been housed in an enriched environment, show increased connectivity between CA1 and cortical areas compared to mice from standard housing. This is the first preliminary demonstration of live-activated neuronal pathways following environmental enrichment in FAD mice. Understanding the activated pathways may unravel the …molecular mechanism underlying environmental enrichment-enhanced neuroplasticity in FAD. Show more

Keywords: Alzheimer's disease, brain plasticity, environmental enrichment, resting state functional MRI

DOI: 10.3233/JAD-2012-111508

Citation: Journal of Alzheimer's Disease, vol. 32, no. 1, pp. 101-107, 2012