Journal of Alzheimer's Disease - Volume 40, issue s1

Authors: Medina, Miguel | Avila, Jesús

Article Type: Editorial

DOI: 10.3233/JAD-140755

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S1-S3, 2014

Authors: Avila, Jesús | Simón, Diana | Díaz-Hernández, Miguel | Pintor, Jesús | Hernández, Félix

Article Type: Review Article

Abstract: The pathology associated with tau protein, tauopathy, has been recently analyzed in different disorders, leading to the suggestion that intracellular and extracellular tau may itself be the principal agent in the transmission and spreading of tauopathies. Tau pathology is based on an increase in the amount of tau, an increase in phosphorylated tau, and/or an increase in aggregated tau. Indeed, phosphorylated tau protein is the main component of tau aggregates, such as the neurofibrillary tangles present in the brain of Alzheimer's disease patients. It has been suggested that intracellular tau could be toxic to neurons in its phosphorylated and/or aggregated …form. However, extracellular tau could also damage neurons and since neuronal death is widespread in Alzheimer's disease, mainly among cholinergic neurons, these cells may represent a possible source of extracellular tau. However, other sources of extracellular tau have been proposed that are independent of cell death. In addition, several ways have been proposed for cells to interact with, transmit, and spread extracellular tau, and to transduce signals mediated by this tau. In this work, we will discuss the role of extracellular tau in the spreading of the tau pathology. Show more

Keywords: Exomas, muscarinic receptors, phosphotau, tau secretion, tau spreading

DOI: 10.3233/JAD-131832

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S7-S15, 2014

Authors: Sayas, C.L. | Ávila, Jesús

Article Type: Review Article

Abstract: During neuronal development, spherical neuroblasts differentiate into mature neurons through the extension of a long axon and several shorter dendrites. Morphological changes that underlie neuronal differentiation are mostly driven by the microtubular cytoskeleton. Regulation of microtubule dynamics and stability during axon and dendrite extension relies on the action of different families of microtubular proteins, such as classical microtubule-associated proteins (MAPs) and microtubule plus-end tracking proteins (+TIPs). This review article addresses recent research on the crosstalk between the main axonal MAPs, tau and MAP1B, and end binding proteins (EBs), the core +TIPs, during axon outgrowth in developing neuronal cells. Furthermore, we …discuss the potential implications of the dysregulation of the interplay between tau and EBs in neurodegenerative disorders such as Alzheimer's disease. Show more

Keywords: Alzheimer's disease, axon outgrowth, MAPs, MAP1B, microtubule dynamics, neurodegeneration, neuronal development, tau, +TIPs

DOI: 10.3233/JAD-132315

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S17-S22, 2014

Authors: Gozes, Illana | Iram, Tal | Maryanovsky, Evgenia | Arviv, Carmit | Rozenberg, Liora | Schirer, Yulie | Giladi, Eliezer | Furman-Assaf, Sharon

Article Type: Research Article

Abstract: NAP (NAPVSIPQ, davunetide) is a microtubule stabilizing peptide drug candidate. Here, we set out to identify NAP-like peptides that provide neuroprotection and reduce tau pathology. NAP-like peptides were derived using publically available search engines, which identified sequence homologies in the microtubule subunit tubulin and in the microtubule associated protein, tau. NATLSIHQ (NAT) and STPTAIPQ were derived from tubulin, and TAPVPMPD (TAP) was derived from tau. All peptides provided neuroprotection against the Alzheimer's disease (AD) toxin, the amyloid-β 1–42 peptide, although NAT and TAP were much more potent than STPTAIPQ. NAT also protected astrocytes, while STPTAIPQ was active only at micromolar …concentrations. Because NAT and TAP were much more potent than STPTAIPQ in neuroprotection, those peptides were also tested for inhibition of tau-like aggregation (the second protein hallmark pathology of AD). Both NAT and TAP inhibited tau-like aggregation, with NAT being active over a very broad concentration range. NAT also protected in vivo in a frontotemporal dementia transgenic mouse model (Tau-Tg), when tested at the age of ~10 months. Results showed significantly decreased levels of the NAP parent protein, activity-dependent neuroprotective protein in the cerebral cortex of the Tau-Tg which was increased back to normal levels by NAT treatment. This was coupled to protection of Brain-Body weight ratio in the compromised Tau-Tg. With AD being the major tauopathy and with tau taking part in frontotemporal dementia, novel NAP derivatives that reduce tauopathy and provide neuroprotection are of basic and clinical interest. Show more

Keywords: Activity-dependent neuroprotective protein (ADNP), aggregation, microtubules, NAP (davunetide), neuroprotection, peptides, tau, tauopathy, tubulin

DOI: 10.3233/JAD-131664

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S23-S36, 2014

Authors: Hanger, Diane P. | Lau, Dawn H.W. | Phillips, Emma C. | Bondulich, Marie K. | Guo, Tong | Woodward, Benjamin W. | Pooler, Amy M. | Noble, Wendy

Article Type: Review Article

Abstract: Tau has a well-established role as a microtubule-associated protein, in which it stabilizes the neuronal cytoskeleton. This function of tau is influenced by tau phosphorylation state, which is significantly increased in Alzheimer's disease and related tauopathies. Disruptions to the cytoskeleton in disease-affected neurons include reduced length and numbers of stable microtubules, and their diminished stability is associated with increased tau phosphorylation in disease. Tau is also localized in the nucleus and plasma membrane of neurons, where it could have roles in DNA repair and cell signaling. Most recently, potential roles for extracellular tau have been highlighted. The release of tau …from neurons is a physiological process that can be regulated by neuronal activity and extracellular tau may play a role in inter-neuronal signaling. In addition, recent studies have suggested that the misfolding of tau in diseased brain leads to abnormal conformations of tau that can be taken up by neighboring neurons. Such a mechanism may be responsible for the apparent prion-like spreading of tau pathology through the brain, which occurs in parallel with clinical progression in the tauopathies. The relationship between tau localization in neurons, tau release, and tau uptake remains to be established, as does the function of extracellular tau. More research is needed to identify disease mechanisms that drive the release and propagation of pathogenic tau and to determine the impact of extracellular tau on cognitive decline in neurodegenerative disease. Show more

Keywords: Alzheimer's disease, endocytosis, microtubules, neurodegeneration, phosphorylation, tau, tau release, tauopathy

DOI: 10.3233/JAD-132054

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S37-S45, 2014

Authors: Saman, Sudad | Lee, Norman C.Y. | Inoyo, Itoro | Jin, Jun | Li, Zhihan | Doyle, Thomas | McKee, Ann C. | Hall, Garth F.

Article Type: Research Article

Abstract: Tau misprocessing to form aggregates and other toxic species has emerged as a major feature in our developing understanding of the etiology and pathogenesis of Alzheimer's disease (AD). The significance of tau misprocessing in AD has been further emphasized by recent studies showing that tau can be secreted from neurons via exosomes and may itself be an important agent in the spreading of neurofibrillary lesions within the brain. Tau secretion occurs most readily under disease-associated conditions in cellular models, suggesting that cellular changes responsible for secretion, possibly including tau oligomerization, could play a key role in the propagation of neurofibrillary …lesions in neurodegenerative disease. Here we show that overexpression of 4R0N human tau in neuroblastoma cells recruits mitochondrial and axonogenesis-associated proteins relevant to neurodegeneration into the exosomal secretion pathway via distinct mechanisms. The recruitment of mitochondrial proteins appears to be linked to autophagy disruption (exophagy) in multiple neurodegenerative conditions but has few known direct links to AD and tau. By contrast, the involvement of synaptic plasticity and axonogenesis markers is highly specific to both tau and AD and may be relevant to the reactivation of developmental programs involving tau in AD and the recently demonstrated ability of secreted tau to establish tissue distribution gradients in CNS neuropil. We also found a highly significant correlation between genes that are significantly downregulated in multiple forms of AD and proteins that have been recruited to exosomes by tau, which we interpret as strong evidence for the central involvement of tau secretion in AD cytopathogenesis. Our results suggest that multiple cellular mechanisms may link tau secretion to both toxicity and neurofibrillary lesion spreading in AD and other tauopathies. Show more

Keywords: Alzheimer's disease, autophagy, endosome, exosome, gene downregulation, mitochondria, morphogen, tau, tau lesion spreading, tau secretion

DOI: 10.3233/JAD-132135

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S47-S70, 2014

Authors: Martinez-Aguila, Alejandro | Fonseca, Begoña | Hernandez, Felix | Díaz-Hernandez, Miguel | Avila, Jesús | Pintor, Jesus

Article Type: Research Article

Abstract: In recent years, in vitro experiments have shown that the spread of Alzheimer's disease is caused by a non-conventional activation of muscarinic receptors by dephosphorylated extracellular tau protein. However, so far, in vivo data to support this hypothesis has not been obtained. The eye provides a good model where cholinergic (muscarinic) transmission can be analyzed. The role of muscarinic receptors in the stimulation of lacrimal gland secretion has already been described, and it has been suggested that acetylcholine is the main transmitter controlling tear secretion. In this project, we have studied the interaction between tau and muscarinic receptors by analyzing …tear secretion in the eyes of white rabbits. Our results show that tau protein increases tear secretion by 47.2% in a similar way to a muscarinic receptor agonist carbachol (84.3%). The use of muscarinic antagonists indicated that tau interacts with M1 and mainly M3 muscarinic receptors. In summary, tau can bind muscarinic receptors in vivo and this may explain the spread of the pathology. Show more

Keywords: Alzheimer's disease, muscarinic receptors, tau, tear secretion

DOI: 10.3233/JAD-132255

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S71-S77, 2014

Authors: de Cristóbal, Javier | García-García, Luis | Delgado, Mercedes | Pérez, Mar | Pozo, Miguel A. | Medina, Miguel

Article Type: Research Article

Abstract: Abnormal levels and hyperphosphorylation of tau protein have been proposed as the underlying cause of a group of neurodegenerative disorders collectively known as ‘tauopathies’. The detrimental consequence is the loss of affinity between this protein and the microtubules, increased production of fibrillary aggregates, and the accumulation of insoluble intracellular neurofibrillary tangles. A similar phenotype can be observed in various preclinical models, which have been generated to study the role of tau protein in neurodegenerative disorders. In this study, we have analyzed the brain metabolic activity in an animal model of tauopathy (tauVLW transgenic mice), which has been previously reported to …mimic some of the phenotypic features of these disorders. By using a non-invasive technique, positron emission tomography (PET), a longitudinal non-clinical follow up study was carried out during most of the lifespan of these transgenic mice, from the youth to the senescence stages. The results obtained point out to an aging-dependent decrease in 18 F-fluoro-deoxyglucose (FDG) uptake in the cerebral areas analyzed, which was already significant at the adult age, i.e., 11 months, and became much more prominent in the oldest animals (19 months old). This observation correlates well with the histopathological observation of neurodegeneration in brain areas where there is overexpression of tau protein. Show more

Keywords: Brain metabolism, longitudinal, neuroimaging, tau protein, transgenic mouse

DOI: 10.3233/JAD-132276

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S79-S89, 2014

Authors: Sahara, Naruhiko | Ren, Yan | Ward, Sarah | Binder, Lester I. | Suhara, Tetsuya | Higuchi, Makoto

Article Type: Short Communication

Abstract: The discovery of tau mutations in frontotemporal dementia has been a key event in neurodegenerative disease research. The rTg4510 mouse line expressing human tau with P301L FTDP-17-tau mutation has been established to understand the role of tau in neurodegeneration. Our histological analyses with tau antibodies and fluorescent tau ligands on rTg4510 mice revealed that tau oligomer formation was distinct from tangle formation. While in vivo imaging of mature tangles is now available, imaging biomarkers for tau oligomers would be useful for clarifying their roles in neurotoxicity and for diagnosing early-stage tau pathology.

Keywords: Antibody, tau ligand, tau oligomers, tau protein, transgenic mice

DOI: 10.3233/JAD-132429

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S91-S96, 2014

Authors: Castillo-Carranza, Diana L. | Gerson, Julia E. | Sengupta, Urmi | Guerrero-Muñoz, Marcos J. | Lasagna-Reeves, Cristian A. | Kayed, Rakez

Article Type: Research Article

Abstract: Neurodegenerative disease is one of the greatest health crises in the world and as life expectancy rises, the number of people affected will continue to increase. The most common neurodegenerative disease, Alzheimer's disease, is a tauopathy, characterized by the presence of aggregated tau, namely in the form of neurofibrillary tangles. Historically, neurofibrillary tangles have been considered the main tau species of interest in Alzheimer's disease; however, we and others have shown that tau oligomers may be the most toxic form and the species responsible for the spread of pathology. We developed a novel anti-tau oligomer-specific mouse monoclonal antibody (TOMA) and …investigated the potential of anti-tau oligomer passive immunization in preventing the toxicity of tau pathology in Htau mice. We injected pure brain-derived tau oligomers intracerebrally in 3-month-old wild-type and Htau mice and investigated the protective effects of a single 60 μg TOMA injection when compared to the same dose of non-specific IgG and found that TOMA conferred protection against the accumulation of tau oligomers and cognitive deficits for up to 1 month after treatment. Additionally, we injected pure brain-derived tau oligomers intracerebrally in 3-month-old wild-type and Htau mice and treated animals with biweekly injections of 60 μg TOMA or non-specific IgG. We found that long-term administration of TOMA was effective as a preventative therapy, inhibiting oligomeric tau and preserving memory function. These results support the critical role of oligomeric tau in disease progression and validate tau oligomers as a potential drug target. Show more

Keywords: Alzheimer's disease, immunotherapy, propagation, seeding, tau oligomers, tauopathies

DOI: 10.3233/JAD-132477

Citation: Journal of Alzheimer's Disease, vol. 40, no. s1, pp. S97-S111, 2014