Journal of Alzheimer's Disease - Volume 37, issue 3

Authors: Gong, Cheng-Xin | Alonso, Alejandra del Carmen

Article Type: Editorial

DOI: 10.3233/JAD-130490

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 465-466, 2013

Authors: Grundke-Iqbal, Inge

Article Type: Other

DOI: 10.3233/JAD-130492

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 467-467, 2013

Authors: Iqbal, Khalid | Bolognin, Silvia | Wang, Xiaochuan | Basurto-Islas, Gustavo | Blanchard, Julie | Tung, Yunn Chyn

Article Type: Review Article

Abstract: Alzheimer's disease is multifactorial and involves several different mechanisms. The sporadic form of the disease accounts for over 99% of the cases. As of yet, there is no practical and widely available animal model of the sporadic form of the disease. In the Alzheimer's disease brain, the lysosomal enzyme asparaginyl endopeptidase is activated and translocated from the neuronal lysosomes to the cytoplasm, probably due to brain acidosis caused by ischemic changes associated with age-associated microinfarcts. The activated asparaginyl endopeptidase cleaves inhibitor-2 of protein phosphatase-2A, I2 PP2A , into I2NTF and I2CTF which translocate to the neuronal cytoplasm and …inhibit the protein phosphatase activity and consequently the abnormal hyperphosphorylation of tau. Employing adeno-associated virus serotype 1 (AAV1) vector containing I2NTF-CTF and transduction of the brains of newborn rat pups with this virus, an animal model has been generated. The AAV1-I2NTF-CTF rats show neurodegeneration and cognitive impairment at 4 months and abnormal hyperphosphorylation and aggregation of tau and intraneuronal accumulation of amyloid-β at 13 months. The AAV1-I2NTF-CTF rats not only offer a disease-relevant model of the sporadic form of Alzheimer's disease but also represent a practical and widely available animal model. This short perspective on the need to focus on and develop the disease-relevant models of the sporadic form of Alzheimer's disease very much reflects the thinking of Inge Grundke-Iqbal who passed away on September 22, 2012 and to whom this article is dedicated. Show more

Keywords: Asparaginyl endopeptidase, non-transgenic rat model of sporadic Alzheimer's disease, protein phosphatase-2A, rat model of sporadic Alzheimer's disease, tau protein, tauopathies

DOI: 10.3233/JAD-130827

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 469-474, 2013

Authors: Iqbal, Khalid | Flory, Michael | Soininen, Hilkka

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a multifactorial disorder that involves several different mechanisms. Over 99% of AD patients suffer from the sporadic form of the disease. Based on cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)1-42 , total tau, and ubiquitin—the markers associated with the histopathological hallmarks of the disease (Aβ plaques and abnormally hyperphosphorylated neurofibrillary tangles)—previous studies identified five subgroups of AD. Here we report the potential diagnostic predictive value of hallucination, hypokinesia, paranoia, rigidity, and tremors in aged individuals for AD and differences in the prevalence of these symptoms in the CSF marker-based subgroups of the disease. Analysis of 196 …clinically diagnosed AD or Alzheimer with Lewy body, and 75 non-AD neurological and non-neurological control cases, all from a single center, showed that the presence of hallucination, hypokinesia, paranoia, rigidity, or tremors individually, or the presence of any of these, could diagnose AD with sensitivities and specificities of 14% and 99%; 30% and 99%; 15% and 99%; 16% and 100%; 16% and 96%; and 47% and 92%, respectively. The pattern of the prevalence of the above symptoms varied from AD subgroup to subgroup. Presence of any of these symptoms, as well as presence of each individual symptom except tremors, significantly differentiated AD subgroups from the predominantly control cluster. These findings encourage the exploration of hallucination, hypokinesia, paranoia, rigidity, and tremors in identifying various subgroups of AD for stratification of patients for clinical trials to develop therapeutic drugs. This study is for the special issue of the Journal of Alzheimer's Disease honoring Inge Grundke-Iqbal who made several seminal contributions in AD research. Show more

Keywords: Alzheimer's disease subgroups, hallucination, hypokinesia, paranoia, rigidity, tremors

DOI: 10.3233/JAD-130899

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 475-481, 2013

Authors: Liu, Chang | Götz, Jürgen

Article Type: Review Article

Abstract: This review is dedicated to Inge Grundke-Iqbal who laid the foundations of the tau field, by isolating tau from the Alzheimer's disease (AD) brain, discovering that tau is hyperphosphorylated, and proving a critical role of protein phosphatase 2A (PP2A) and its endogenous inhibitor I2 PP2A in this process. This memorial starts with a few personal notes, and then covers how subcellular fractionation helped in isolating tau. We review in detail the role of PP2A and its endogenous inhibitor in tau phosphorylation. We discuss the role that methylation and phosphorylation have in regulating PP2A activity. We add what we have …contributed to understanding the role of tau and PP2A in AD using PP2A transgenic and knockout models, and conclude by addressing two underexplored areas in tau research: tau's non-canonical functions and the role distinct tau isoforms have in a physiological context. Show more

Keywords: Alzheimer's disease, frontotemporal dementia, nucleus, protein phosphatase 2A, SFPQ, tau, transcription factor

DOI: 10.3233/JAD-130503

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 483-494, 2013

Authors: Wang, Shan | Wu, Jing | Nie, Sheng-Dan | Bereczki, Erika | Pei, Jin-Jing

Article Type: Review Article

Abstract: Recent evidence implicated aberrant mammalian target of rapamycin (mTOR)-dependent signaling in both Alzheimer's disease (AD) and brain tumors. This review focuses on the potential mechanisms shared by both neurodegeneration and carcinogenesis. In particular, attention was paid to the possible roles of mTOR-dependent signaling in these two fundamental pathophysiological processes. We hypothesize that common stresses could lead either to progressive degeneration or uncontrolled carcinogenesis via cell type specific upregulation of mTOR-dependent signaling in the central nervous system while mTOR-mediated carcinogenesis might permit glial cells to escape from degeneration.

Keywords: Alzheimer's disease, carcinogenesis, mTOR, neurodegeneration

DOI: 10.3233/JAD-130641

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 495-505, 2013

Authors: Hernández, Félix | García-García, Esther | Avila, Jesús

Article Type: Research Article

Abstract: Inge Grundke-Iqbal and Khalid Iqbal found a connection between microtubule associated tau and Alzheimer's disease. They described that abnormally phosphorylated tau is a component of the paired helical filaments found in the disease. Afterwards they described that tau hyperphosphorylation prevents microtubule assembly. Now trying to complement the relationship between microtubules and tau phosphorylation, we have commented on the effect of microtubule disassembly on tau phosphorylation. In this study, we investigated the role of microtubule depolymerization induced by nocodazole on tau phosphorylation in human neuroblastoma SH-SY5Y cells. Our results indicate that nocodazole provokes tau phosphorylation mediated by GSK3, as determined by …using AT-8 or Tau-1 antibodies. Interestingly, total GSK3β and GSK3β phosphorylation on Ser-9 are not altered during nocodazole treatment. In addition, microtubule stabilization with taxol had similar effects, likely because taxol and tau compete for the same binding sites on microtubules, and in the presence of taxol, tau could be detached from microtubules. Thus, unbound tau from microtubles can be phosphorylated by GSK3, even if the activity of GSK3 is not altered, probably because tau unbound to microtubules could be a better substrate for the kinase than microtubule-associated tau. These findings suggest that microtubule depolymerization can be a primary event in neurodegenerative disorders like Alzheimer's disease and that tau phosphorylation takes place afterwards. Show more

Keywords: Disassembly, GSK3, microtubules, phosphorylation, tau

DOI: 10.3233/JAD-130545

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 507-513, 2013

Authors: Wu, Yuan-Yuan | Wang, Xiong | Tan, Lu | Liu, Dan | Liu, Xing-Hua | Wang, Qun | Wang, Jian-Zhi | Zhu, Ling-Qiang

Article Type: Research Article

Abstract: Cholinergic dysfunction plays a crucial role in the memory deterioration of Alzheimer's disease, but the molecular mechanism is not fully understood. By employing a widely recognized cholinergic dysfunction rat model that was produced by intraperitoneal injection of scopolamine, we investigated the mechanisms underlying scopolamine-induced memory deficits. We found that scopolamine caused spatial learning and memory deficits that involved activation of glycogen synthase kinase-3β (GSK-3β) and impairments of dendrite arborization and spine formation/maturation associated with alterations of AMPAR, Homer1, and CREB. Pretreatment by intraperitoneal injection of lithium, an inhibitor of GSK-3, for one week prevented the synaptic changes and the learning …and memory deficits induced by scopolamine. Lithium treatment also activated cholineacetyltransferase and inhibited acetylcholinesterase, which might have also contributed to the improved memory. Our findings suggest that GSK-3β may be a key molecular mediator of cholinergic synaptic dysfunction, and that inhibition of GSK-3β by lithium may be promising in protecting cholinergic synaptic functions. Show more

Keywords: AMPA receptors, cholinergic dysfunction, GSK-3β, Homer1, lithium, scopolamine

DOI: 10.3233/JAD-130521

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 515-527, 2013

Authors: Qian, Wei | Jin, Nana | Shi, Jianhua | Yin, Xiaomin | Jin, Xiaoxia | Wang, Shibao | Cao, Maohong | Iqbal, Khalid | Gong, Cheng-Xin | Liu, Fei

Article Type: Research Article

Abstract: Microtubule-associated protein tau is found to be accumulated and aggregated in the brains of individuals with Alzheimer's disease and related tauopathies. Dual-specificity tyrosine-phosphorylation regulated kinase 1A (Dyrk1A) is overexpressed in Down syndrome and may play a critical role in the early onset of tau pathology in this disease. To investigate the effect of Dyrk1A on tau expression, we co-expressed different isoforms of tau with Dyrk1A in HEK-293FT cells and measured the mRNA and protein levels of tau using RT-PCR and Western blots, respectively. We further investigated the mechanism of regulation of tau expression by Dyrk1A. We found that Dyrk1A enhanced …tau expression in a dose-dependent manner. The enhancement did not require the kinase activity of Dyrk1A. Dyrk1A increased the expression of tau isoforms containing exon 10 to a larger extent than isoforms lacking exon 10. The expression of endogenous tau in neuronal cells was also regulated by Dyrk1A, and increased tau levels were found in the brains of Ts65Dn mice that overexpress Dyrk1A due to partial trisomy of chromosome 16. Dyrk1A did not enhance tau gene transcription, but increased tau mRNA stability. These results suggest that Dyrk1A enhances tau expression by stabilizing its mRNA and provides a novel insight into the regulation of tau expression and a molecular mechanism of tauopathies. Show more

Keywords: Alzheimer's disease, Down syndrome, Dyrk1A, mRNA stability, tau

DOI: 10.3233/JAD-130824

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 529-538, 2013

Authors: Beharry, Cindy | Alaniz, Maria Eugenia | Alonso, Alejandra del Carmen

Article Type: Research Article

Abstract: A key characteristic of Alzheimer's disease and other tauopathies is the progressive accumulation of neurofibrillary tangles mainly composed of hyperphosphorylated tau protein. In the present study, we use transgenic Drosophila melanogaster as a model to analyze in vivo the effect of expressing pseudophosphorylated tau (S199E/T212E/T231E/S262E tau) on pathological human tau (PH-tau) and on the FTDP-17 mutant R406W (PH-tauR406W). We used two different inducers that produced different levels of tau expression. The expression of these forms of tau did not significantly affect the lifespan of the flies. Flies expressing PH-tau displayed a clear locomotor dysfunction compared to those expressing normal tau …regardless of the level of expression. At lower level of expression, this pathological phenotype was found to be age-dependent. At 35 days old, PH-tau flies showed the strongest locomotor impairment compare to flies expressing human tau or control flies (46%, 18% and 18% of flies remained on the bottom of the vials, respectively). At higher levels of expression, PH-tau flies showed these defects at seven days of age and the dysfunction also became significant for flies expressing tauR406W and PH-tauR406W. Whole brain immunochemistry analysis revealed that PH-tau as well as PH-tauR406W appeared to have abnormal mushroom body structures, critical structures involved in olfactory learning and memory in Drosophila. Severe olfactory learning deficits were induced by the expression of PH-tau. Taken together, our findings demonstrate that PH-tau induced a toxic effect in Drosophila, as flies develop both an abnormal motor deficit, associated with disruption of the mushroom body neurons, and impaired olfactory learning. Show more

Keywords: Alzheimer's disease model, behavior, hyperphosphorylation, neurodegeneration, tau, transgenic Drosophila

DOI: 10.3233/JAD-130617

Citation: Journal of Alzheimer's Disease, vol. 37, no. 3, pp. 539-550, 2013