Journal of Alzheimer's Disease - Volume 47, issue 1

Authors: Colijn, Mark A. | Grossberg, George T.

Article Type: Review Article

Abstract: Subjective cognitive impairment (SCI) refers to concerns regarding one’s cognitive functioning in the absence of objective evidence of impairment, and may represent an early stage of Alzheimer’s disease. However, as not all individuals with SCI cognitively decline, there is growing interest in the early identification of those individuals with SCI who are most at risk of developing Alzheimer’s disease. One promising method of early identification involves the use of biomarkers that are known to be associated with the pathophysiology of the disease; in particular, markers of amyloid and tau accumulation. While there has been substantial research on amyloid and tau …biomarkers in the context of mild cognitive impairment (MCI), only recently has attention shifted to SCI, which may represent an even earlier stage in the disease course. The purpose of this paper is to qualitatively review the literature on amyloid and tau biomarkers in SCI. A brief discussion of non-amyloid/tau biomarkers is also included. Not surprisingly, we found that amyloid and tau biomarker profiles become increasingly abnormal from SCI, to MCI, to Alzheimer’s disease. Additionally, although amyloid and tau biomarkers appear to be unable to differentiate between SCI and healthy controls, there is some evidence to suggest that they may be able to differentiate between those individuals with SCI who cognitively decline over time and those who do not. While this finding has potential clinical implications, achieving optimal predictive value will likely require further research into the use of numerous biomarkers in combination. Show more

Keywords: Alzheimer’s disease, amyloid, biological markers, dementia, mild cognitive impairment, Pittsburgh compound B, positron emission tomography, prodromal symptoms, tau proteins, tauopathies

DOI: 10.3233/JAD-150180

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 1-8, 2015

Authors: Moosavi, Behrooz | Mousavi, Bibimaryam | Macreadie, Ian G.

Article Type: Review Article

Abstract: The amyloid-β peptide (Aβ ) and the phosphorylated protein tau have been widely implicated in Alzheimer’s disease and are the focus of most research. Both agents have been extensively studied in mammalian cell culture and in animal studies, but new research is focusing on yeast models. Yeast are eukaryotes, just like us, and are amenable to effects and expression of Aβ and tau and appear able to ‘report’ with considerable relevance on the effects of these biomolecules. The use of yeast enables powerful new approaches to understanding how to overcome the effects of Aβ and tau, and …such advances could lead to new therapies to prevent the progression of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid, protein aggregation, tau protein, yeasts

DOI: 10.3233/JAD-150173

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 9-16, 2015

Authors: Groblewska, Magdalena | Muszyński, Paweł | Wojtulewska-Supron, Aleksandra | Kulczyńska-Przybik, Agnieszka | Mroczko, Barbara

Article Type: Review Article

Abstract: Calcium ions are crucial in the process of information transmission and integration in the central nervous system (CNS). These ions participate not only in intracellular mechanisms but also in intercellular processes. The changes in the concentration of Ca2 + ions modulate synaptic transmission, whereas neuronal activity induces calcium ion waves. Disturbed calcium homeostasis is thought to be one of the main features in the pathophysiology of Alzheimer’s disease (AD), and AD pathogenesis is closely connected to Ca2 + signaling pathways. The effects of changes in neuronal Ca2 + are mediated by neuronal calcium sensor (NCS) proteins. It has been revealed …that NCS proteins, with special attention to visinin-like protein 1 (VILIP-1), might have a connection to the etiology of AD. In the CNS, VILIP-1 influences the intracellular neuronal signaling pathways involved in synaptic plasticity, such as cyclic nucleotide cascades and nicotinergic signaling. This particular protein is implicated in calcium-mediated neuronal injury as well. VILIP-1 also participates in the pathological mechanisms of altered Ca2 + homeostasis, leading to neuronal loss. These findings confirm the utility of VILIP-1 as a useful biomarker of neuronal injury. Moreover, VILIP-1 plays a vital role in linking calcium-mediated neurotoxicity and AD-type pathological changes. The disruption of Ca2 + homeostasis caused by AD-type neurodegeneration may result in the damage of VILIP-1-containing neurons in the brain, leading to increased cerebrospinal fluid levels of VILIP-1. Thus, the aim of this overview is to describe the relationships of the NCS protein VILIP-1 with the pathogenetic factors of AD and neurodegenerative processes, as well as its potential clinical usefulness as a biomarker of AD. Moreover, we describe the current and probable therapeutic strategies for AD, targeting calcium-signaling pathways and VILIP-1. Show more

Keywords: Alzheimer’s disease, biomarkers, brain injury, neurodegeneration, visinin-like protein-1

DOI: 10.3233/JAD-150060

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 17-32, 2015

Authors: Atwood, Craig S. | Bowen, Richard L.

Article Type: Research Article

Abstract: Early-onset familial Alzheimer’s disease (EOFAD) and late-onset sporadic AD (LOSAD) both follow a similar pathological and biochemical course that includes: neuron and synapse loss and dysfunction, microvascular damage, microgliosis, extracellular amyloid-β deposition, tau phosphorylation, formation of intracellular neurofibrillary tangles, endoreduplication and related cell cycle events in affected brain regions. Any mechanistic explanation of AD must accommodate these biochemical and neuropathological features for both forms of the disease. In this insight paper we provide a unifying hypothesis for EOFAD and LOSAD that proposes that the aberrant re-entry of terminally differentiated, post-mitotic neurons into the cell division cycle is a common pathway that explains …both early and late-onset forms of AD. Cell cycle abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles, and explain the biochemical (e.g. tau phosphorylation), neuropathological (e.g. neuron hypertrophy; polypoidy) and cognitive changes observed in EOFAD and LOSAD. Genetic mutations in AβPP, PSEN1 , and PSEN2 that alter amyloid-β precursor protein and Notch processing drive reactivation of the cell cycle in EOFAD, while age-related reproductive endocrine dyscrasia that upregulates mitogenic TNF signaling and AβPP processing toward the amyloidogenic pathway drives reactivation of the cell cycle in LOSAD. In essence, AβPP and presenilin mutations initiate early, what endocrine dyscrasia initiates later: aberrant cell cycle re-entry of post-mitotic neurons leading to neurodegeneration and cognitive decline in AD. Inhibition of cell cycle re-entry in post-mitotic neurons may be a useful therapeutic strategy to prevent, slow or halt disease progression. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, cell cycle re-entry, endocrine dyscrasia, hypothalamic-pituitarygonadal axis, luteinizing hormone, menopause, neuron presenilin, tau

DOI: 10.3233/JAD-143210

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 33-47, 2015

Authors: Lee, Sangmook | Sohal, Ikjot S. | Therrien, Mikaela A. | Pal, Anoop K. | Bello, Dhimiter | Shea, Thomas B.

Article Type: Short Communication

Abstract: Photocopying in offices and printing centers releases nanoparticles that can reach the brain following inhalation. We examined whether subcytotoxic levels of airborne photocopy-emitted nanoparticles could potentiate perturbation of synaptic signaling in cultured neurons following exposure to amyloid-β (Aβ ). Signaling was only transiently inhibited by Aβ or nanoparticles individually, but remained statistically reduced in cultures receiving both after 24 h. In vitro and in vivo studies with copier emitted nanoparticles have consistently demonstrated inflammation, oxidative stress, and cytotoxicity. Since Aβ can accumulate years before cognitive decline, subcytotoxic levels of nanoparticles are one factor that could potentiate …Aβ -induced impairment of synaptic activity during these early stages. Show more

Keywords: Amyloid-β, multi-electrode arrays, nanoparticles, signaling, neurotoxicology

DOI: 10.3233/JAD-150099

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 49-54, 2015

Authors: Heymann, Anthony D. | Ravona-Springer, Ramit | Moshier, Erin L. | Godbold, James | Beeri, Michal Schnaider

Article Type: Short Communication

Abstract: The pleiotropic contribution of statins on cognition is uncertain. From 840 patients in the cohort from the Israel Diabetes and Cognitive Decline Study, we identified 61 non-statin users and compared them with 45 patients who had used statins at least 90% of the time. Analysis of covariance was performed to compare mean cognitive z-scores between statin users and non-users while adjusting for socio-demographic, diabetes-related, and cardiovascular covariates which included change in cholesterol by year. Overall cognition, memory, and executive function was found to be significantly better in statin users (p  <  0.0008). This suggests a positive effect of statins on …cognitive function of type 2 diabetes patients that is independent of cholesterol levels. Show more

Keywords: All cognitive disorders/dementia, Alzheimer’s disease, case control studies, diabetes

DOI: 10.3233/JAD-142571

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 55-59, 2015

Authors: Ren, Qing-Guo | Wang, Yan-Juan | Gong, Wei-Gang | Xu, Lin | Zhang, Zhi-Jun

Article Type: Research Article

Abstract: Here, we investigated the effect of escitalopram pretreatment on protein kinase A (PKA)-induced tau hyperphosphorylation and spatial memory deficits in rats using western blot and behavioral tests, respectively. We demonstrated that escitalopram effectively ameliorated tau hyperphosphorylation and the spatial memory deficits induced by PKA activation. We measured the total and activity-dependent Ser9-phosphorylated levels of glycogen synthase kinase (GSK)-3β in hippocampal extracts. No significant change in the total level of GSK-3β was observed between the different groups. However, compared with forskolin injection alone, pretreatment with escitalopram increased the level of Ser9-phosphorylated GSK-3β . We also demonstrated that escitalopram increased …Akt phosphorylation at Ser473 (the active form of Akt). Furthermore, we identified other important kinases and phosphatases, such as protein phosphatase 2A, extracellular signal-regulated kinases 1 and 2, and MAP kinase kinase-1/2, that have previously been reported to play a crucial role in tau phosphorylation; however, we did not detect any significant change in the activation of these kinases or phosphatases in our study. We unexpectedly demonstrated that forskolin caused anxiety-like behavior in rats, and pretreatment with escitalopram did not significantly ameliorate the anxiety-like behavior induced by forskolin. These data provide the first evidence that escitalopram ameliorates forskolin-induced tau hyperphosphorylation and spatial memory impairment in rats; these effects do not occur via the anti-anxiety activity of escitalopram but may involve the Akt/GSK-3β signaling pathway. Show more

Keywords: Alzheimer’s disease, escitalopram, PKA, tau

DOI: 10.3233/JAD-143012

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 61-71, 2015

Authors: Li, Shanshan | Geiger, Nicholas H. | Soliman, Mahmoud L. | Hui, Liang | Geiger , Jonathan D. | Chen, Xuesong

Article Type: Research Article

Abstract: Intraneuronal accumulation and extracellular deposition of amyloid-β (Aβ) protein continues to be implicated in the pathogenesis of Alzheimer’s disease (AD), be it familial in origin or sporadic in nature. Aβ is generated intracellularly following endocytosis of amyloid-β protein precursor (AβPP), and, consequently, factors that suppress AβPP internalization may decrease amyloidogenic processing of AβPP. Here we tested the hypothesis that caffeine decreases Aβ generation by suppressing AβPP internalization in primary cultured neurons. Caffeine concentration-dependently blocked low-density lipoprotein (LDL) cholesterol internalization and a specific adenosine A3 receptor (A3 R) antagonist as well as siRNA knockdown of A3 Rs mimicked the effects …of caffeine on neuronal internalization of LDL cholesterol. Further implicating A3 Rs were findings that a specific A3 R agonist increased neuronal internalization of LDL cholesterol. In addition, caffeine as well as siRNA knockdown of A3 Rs blocked the ability of LDL cholesterol to increase Aβ levels. Furthermore, caffeine blocked LDL cholesterol-induced decreases in AβPP protein levels in neuronal plasma membranes, increased surface expression of AβPP on neurons, and the A3 R antagonist as well as siRNA knockdown of A3 Rs mimicked the effects of caffeine on AβPP surface expression. Moreover, the A3 R agonist decreased neuronal surface expression of AβPP. Our findings suggest that caffeine exerts protective effects against amyloidogenic processing of AβPP at least in part by suppressing A3 R-mediated internalization of AβPP. Show more

Keywords: Adenosine A_3 receptor, Alzheimer’s disease, amyloid-β , amyloid-β protein precursor, caffeine, endocytosis, LDL cholesterol

DOI: 10.3233/JAD-142223

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 73-83, 2015

Authors: Huang, Rong | Wang, Pin | Han, Jing | Xia, Wenqing | Cai, Rongrong | Sun, Haixia | Sun, Jie | Wang, Shaohua

Article Type: Research Article

Abstract: Background: Insulin-like growth factor (IGF)-1, through insulin/IGF-1 signaling pathway, is involved in the pathogenesis of type 2 diabetes mellitus (T2DM) and Alzheimer’s disease. Objective: This study aimed to assess the association of serum IGF-1 and IGF binding protein (IGFBP)-3 levels with cognition status and to determine whether IGF-1 rs972936 polymorphism is associated with T2DM with mild cognitive impairment (MCI). Methods: A total of 150 T2DM patients, 75 satisfying the MCI diagnostic criteria and 75 exhibiting healthy cognition, were enrolled in this study. The cognitive function of the subjects was extensively assessed. Serum IGF-1 and IGFBP-3 …levels were measured through enzyme-linked immunosorbent assay; IGF-1/IGFBP-3 molar ratio was calculated. Single nucleotide polymorphisms of the IGF-1-(rs972936) gene were analyzed. Results: Serum IGF-1/IGFBP-3 molar ratio in MCI patients was significantly lower than that in the control group (p  = 0.003). Significant negative correlations were found between IGF-1/IGFBP-3 molar ratio and Trail Making Test A and B (TMT-A and TMT-B) scores (p  = 0.003; p  <  0.001, respectively), which indicated executive function. Further multiple step-wise regression analysis revealed that the TMT-A or TMT-B score was significantly associated only with serum IGF-1/IGFBP-3 molar ratio (p  = 0.016; p  <  0.001, respectively). No significant difference was found in the genotype or allele distribution of IGF-1 rs972936 polymorphism between MCI and control groups. Conclusions: A low serum IGF-1/IGFBP-3 molar ratio is associated with the pathogenesis of MCI, particularly executive function in T2DM populations. Further investigation with a large population size should be conducted to confirm this observed association. Show more

Keywords: Insulin-like growth factor-1, mild cognitive impairment, polymorphism, type 2 diabetes mellitus

DOI: 10.3233/JAD-150071

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 85-94, 2015

Authors: Lagarde, Julien | Hamelin, Lorraine | Hahn, Valé | Habert, Marie-Odile | Seilhean, Danielle | Duyckaerts, Charles | Sarazin, Marie

Article Type: Research Article

Abstract: The impact of neuropathological lesions on the clinical symptoms and progression of Lewy body disease (LBD) remains unclear. To address this issue, we describe two illustrative cases of autopsy-proven LBD that presented atypical phenotypes of progressive supranuclear palsy syndrome and semantic dementia. Postmortem examination revealed diffuse LBD with massive brainstem involvement in case 1, whereas Lewy bodies predominated in the amygdala and neocortex in case 2. Alzheimer’s disease pathology was present in both cases, and TDP-43 inclusions were noted in case 2. These cases illustrate two contrasted clinical presentations and highlight the heterogeneity within the underlying proteinopathies of neurodegenerative diseases.

Keywords: Alzheimer’s disease, Lewy body, neuropathology, neuropsychology, progressive, supranuclear palsy

DOI: 10.3233/JAD-150203

Citation: Journal of Alzheimer's Disease, vol. 47, no. 1, pp. 95-101, 2015