Alzheimer's disease (AD) is characterized by extracellular beta-amyloid (Abeta(42))-containing plaques and intracellular neurofibrillary tangles. The latter are composed of hyperphosphorylated filamentous aggregates of the microtubule-associated protein tau. Previously we demonstrated pathological interactions between these two histopathological hallmarks using human SH-SY5Y neuroblastoma cells overexpressing wild-type and mutant forms of human tau. Exposure to pre-aggregated forms of Abeta(42) caused both the formation of AD-like tau-containing filaments and a decreased solubility of tau, both of which were prevented by mutating the S422 phospho-epitope of tau. Here, we expressed additional tau mutants in SH-SY5Y cells to assess the role of phosphorylation and cleavage sites of tau in tau aggregation. We found that the Abeta(42)-mediated decrease in tau solubility depends on the interplay of distinct phospho-epitopes of tau and not only on phosphorylation of the S422 epitope.
"We raised an antibody to the S422 phosphorylation site in tau, a disease-specific phospho-epitope that is associated with tau misfolding (Bussiere et al., 1999; Pennanen and Gö tz, 2005; Guillozet-Bongaarts et al., 2006). Tau/pS422 is prominent in early stages of Alzheimer's disease and persists until late-stage disease, making it an attractive target for antibody therapeutics (Guillozet-Bongaarts et al., 2006; Vana et al., 2011). "
"To determine a causal role for tau, we stably expressed both wild-type and P301L human tau in human SH-SY5Y neuroblastoma cells, an established cell culture model of tau pathology (Pennanen and Gotz, 2005). The cells were differentiated by two independent methods, mitomycin C-mediated cell cycle arrest or neuronal differentiation with retinoic acid. "
[Show abstract][Hide abstract] ABSTRACT: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are complex human brain disorders that affect an increasing number of people worldwide. With the identification first of the proteins that aggregate in AD and FTLD brains and subsequently of pathogenic gene mutations that cause their formation in the familial cases, the foundation was laid for the generation of animal models. These recapitulate essential aspects of the human conditions; expression of mutant forms of the amyloid-β protein-encoding APP gene in mice reproduces amyloid-β (Aβ) plaque formation in AD, while that of mutant forms of the tau-encoding microtubule-associated protein tau (MAPT) gene reproduces tau-containing neurofibrillary tangle formation, a lesion that is also prevalent in FTLD-Tau. The mouse models have been complemented by those in lower species such as C. elegans or Drosophila, highlighting the crucial role for Aβ and tau in human neurodegenerative disease. In this review, we will introduce selected AD/FTLD models and discuss how they were instrumental, by identifying deregulated mRNAs, miRNAs and proteins, in dissecting pathogenic mechanisms in neurodegenerative disease. We will discuss some recent examples, which includes miRNA species that are specifically deregulated by Aβ, mitochondrial proteins that are targets of both Aβ and tau, and the nuclear splicing factor SFPQ that accumulates in the cytoplasm in a tau-dependent manner. These examples illustrate how a functional genomics approach followed by a careful validation in experimental models and human tissue leads to a deeper understanding of the pathogenesis of AD and FTLD and ultimately, may help in finding a cure.
Frontiers in Physiology 08/2012; 3:320. DOI:10.3389/fphys.2012.00320 · 3.53 Impact Factor
"The identification of phosphorylation sites crucial for tau's dissociation and aggregation is believed to help identify kinases and phosphatases involved in its hyperphosphorylation and dephosphorylation respectively (Ferrari et al., 2003; BJP Tau-targeted treatment of Alzheimer's disease British Journal of Pharmacology (2012) 165 1246–1259 1251 Hoerndli et al., 2004; Pennanen and Gotz, 2005; Steinhilb et al., 2007) (Figure 3). These enzymes present themselves as excellent targets for a therapeutic intervention in AD and related dementias (Iqbal and Grundke-Iqbal, 2008). "
[Show abstract][Hide abstract] ABSTRACT: With populations ageing worldwide, the need for treating and preventing diseases associated with high age is pertinent. Alzheimer's disease (AD) is reaching epidemic proportions, yet the currently available therapies are limited to a symptomatic relief, without halting the degenerative process that characterizes the AD brain. As in AD cholinergic neurons are lost at high numbers, the initial strategies were limited to the development of acetylcholinesterase inhibitors, and more recently the NMDA receptor antagonist memantine, in counteracting excitotoxicity. With the identification of the protein tau in intracellular neurofibrillary tangles and of the peptide amyloid-β (Aβ) in extracellular amyloid plaques in the AD brain, and a better understanding of their role in disease, newer strategies are emerging, which aim at either preventing their formation and deposition or at accelerating their clearance. Interestingly, what is well established to combat viral diseases in peripheral organs - vaccination - seems to work for the brain as well. Accordingly, immunization strategies targeting Aβ show efficacy in mice and to some degree also in humans. Even more surprising is the finding in mice that immunization strategies targeting tau, a protein that forms aggregates in nerve cells, ameliorates the tau-associated pathology. We are reviewing the literature and discuss what can be expected regarding the translation into clinical practice and how the findings can be extended to other neurodegenerative diseases with protein aggregation in brain.
British Journal of Pharmacology 11/2011; 165(5):1246-59. DOI:10.1111/j.1476-5381.2011.01713.x · 4.84 Impact Factor
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