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Alzheimer's disease is the most common form of dementia, affecting approximately 50 million people worldwide as of 2018 – a number expected to reach 152 million in 2050.1 The neuropathology of Alzheimer's disease is characterized by the accumulation of amyloid plaques and neurofibrillary tangles outside and inside neurons respectively. Healthy amyloid precursor protein (APP) is cleaved to pathogenic beta-amyloid (Aβ) peptides through the sequential action of α-, β-, and γ-secretases. Similarly, tau protein is hyperphosphorylated by GSK3 and other kinases to first form paired helical filaments and subsequently neurofibrillary tangles (NFTs).
Here you can take a deeper look at the disease and its pathphysiology, as well as a better understanding of the antibodies, kits, reagents, and other tools you need for your research.
Alzheimer's disease is characterized by the presence of neurotoxic Aβ plaques in the brain. These plaques are formed by monomeric Aβ spontaneously assembling into soluble oligomers, which cluster together to form insoluble fibrils. Evidence suggests a role for both soluble oligomers and insoluble fibrils in Alzheimer’s disease pathology, but their exact contributions are still under debate. Here we cover the generation of Aβ from APP and how structural variation of Aβ may explain the complex pathology of Alzheimer’s disease.
Aβ peptides are produced by the proteolytic cleavage of APP by enzyme complexes α, β, and γ-secretases. APP cleavage occurs via two distinct pathways (Figure 1). The non-amyloidogenic pathway provides beneficial neurotrophic effects and the amyloidogenic pathway produces neurotoxic Aβ peptides. The Aβ peptides formed via the amyloidogenic pathway can misfold and aggregate to form deposits that contribute to Alzheimer’s disease pathology.
Figure 1. The non-amyloidogenic and amyloidogenic pathways of APP processing.
The non-amyloidogenic pathway
The non-amyloidogenic pathway involves cleavage of APP by α-secretase to generate two fragments; an 83 amino acid C-terminal fragment (C83) that remains in the membrane and an N-terminal ectodomain (sAPPα) that is released into the extracellular medium.
Three enzymes have been identified with α-secretase activity: ADAM9, ADAM10, and ADAM17.2 Importantly, cleavage of APP by α-secretase occurs within the Aβ domain and consequently prohibits Aβ peptide production.
Of note, the C83 membrane fragment can be subsequently cleaved by γ-secretase to produce a short fragment called P3 peptide and a C terminal fragment (CTF). To date, the P3 peptide is believed to be pathologically irrelevant.3
The amyloidogenic pathway
The amyloidogenic pathway leads to neurotoxic Aβ generation. β-secretase (BACE1) mediates the first proteolysis step, which releases a large N-terminal ectodomain (sAPPβ) into the extracellular medium. A 99-amino acid C terminal fragment (C99) remains in the membrane.4–6
The newly exposed C99 N-terminus corresponds to the first amino acid of Aβ. Successive cleavage of this fragment by γ-secretase (between residues 38 and 43) releases the Aβ peptide. γ-secretase is a complex of enzymes consisting of presenilin 1 or 2 (PS1 and PS2), nicastrin, anterior pharynx defective (APH-1) and presenilin enhancer 2 (PEN2).7–11
Most of the Aβ peptides are 40 residues in length (Aβ 1–40), with a small percentage containing 42 residues (Aβ 1–42). Aβ 1–42 is considered the more neurotoxic form because the extra two amino acids provide a greater tendency to misfold and subsequently aggregate.12 Elevated plasma levels of Aβ 1–42 have been correlated with Alzheimer’s disease.13
Targeting Aβ accumulation by slowing its production is gaining importance in the goal to slow down the progression of Alzheimer’s disease. Blocking APP cleavage is made possible due to access to several β-secretase inhibitors.
Table 1. Commonly used inhibitors targeting β-secretase and Aβ production.
β-Secretase Inhibitor II (Z-VLL-CHO)
Peptidyl β-secretase inhibitor (reversible). Corresponds to the VNL-DA cleavage site on APP.14
Potent and selective BACE-1 inhibitor (Ki = 26.1 nM), about 14-fold selectivity over BACE-2 (Ki = 372 nM).15
Highly potent BACE-1 inhibitor with IC50 = 610 pM (primary neuron cultures from mice), 310 pM (primary neuron cultures from guinea pigs), and 80 pM (SH-SY5Y cells over-expressing AβPP).16
Selective β-secretase inhibitor. Shows neuroprotective effects against Aβ(25-35)-induced cell death.17
Potent and selective BACE-1 inhibitor (IC50 = 20.3 nM for recombinant hBACE-1).18
Potent Ca2+ channel blocker that promotes Aβ clearance from the brain and reduced tau hyperphosphorylation.19
Selective, potent β-secretase 1 inhibitor (IC50 = 13 nM).20
Table 2. Recommended tools to study Aβ in Alzheimer's disease.
One barrier to understanding the role of Aβ in Alzheimer’s disease is the lack of correlation between Aβ in the brain and the cognitive ability of patients. For example, some patients with Aβ deposits show no symptoms of Alzheimer’s disease at all.21,22
The answer to Alzheimer’s disease heterogeneity may lie in structural variations of Aβ, which can form polymorphic Aβ oligomers in a process known as segmental polymorphism. This is where the segments that form beta sheets vary between different fibril structures.23–25
It is therefore likely that, like prion diseases, unique forms of structurally distinct Aβ are deposited in different places and at different times in the brains of Alzheimer’s disease patients. However, as yet it remains unclear which types of deposit are more closely linked with the cognitive symptoms of the disease.26
The need for conformation-specific antibodies
With increasing evidence to support the biomedical importance of Aβ structural variation, conformation-specific Aβ imaging reagents will play a central role in the future of Alzheimer’s research.
Research in humans has shown the clinical relevance of Aβ structural variation. Tissue taken from two Alzheimer’s disease patients with distinct clinical histories revealed that each patient had a predominant Aβ fibril structure; however, the dominant structure was different in each patient.27
Studies in mice and cultured cells have also supported the biological relevance of Aβ structural variation. Structurally distinct Aβ fibrils cause varying levels of toxicity in neuronal cultures, while mice given Aβ from different sources develop distinct patterns of Aβ deposition within the brain.28,29
Furthermore, the complexity of Aβ structure is convincingly reflected by the immune system, with research showing that the antibodies produced in response to Aβ fibrils are diverse, reflecting their structural variation.26,30
Considering all evidence, it is becoming increasingly clear that a single antibody will not be enough to study or target all the possible pathological aggregates of Aβ contributing to Alzheimer’s disease. This makes conformation-specific Aβ antibodies an essential tool for the future of Alzheimer’s disease research.31–34
In collaboration with Professor Charles Glabe (UC Irvine), we developed rabbit monoclonal antibodies against Aβ 1–42 fibrils that can distinguish conformational variation in amyloid structures.
Table 3. Antibody reactivity in human and mouse Alzheimer's disease brain.
Human Alzheimer's brain specificity shown by IHC**
Alzheimer's mouse model* brain specificity shown by IHC**
Frontal cortex plaques
Layer V cortical and CA1 pyramidal neurons
Subset of frontal cortex plaques
Vascular amyloid deposits
Frontal cortex plaques
Intracellular/nuclear, frontal cortex plaques
Layer V cortical neurons
Frontal cortex plaques
Layer V cortical neurons (intracellular deposits)
Frontal cortex plaques
Layer V cortical neurons (intracellular deposits)
Frontal cortex plaques
Layer V cortical neurons, hippocampal plaques
*14 month-old 3xTg-AD mouse model of Alzheimer's disease
** IHC shown in Hatami et al. 2014
A brief introduction to the tau protein and how it contributes to Alzheimer's disease.
Under normal circumstances, tau is a microtubule-associated protein (MAP) involved in microtubule stabilization. However, it is also a multi-functional protein with a critical role in certain neurodegenerative disorders including Alzheimer's disease.35
The tau protein is highly soluble, expressed in neurons, oligodendrocytes, and astrocytes within the central nervous system (CNS) and peripheral nervous system (PNS).36,37
It is primarily found in axons where it regulates microtubule polymerization and stabilization. However, its broad selection of binding partners suggests that it has multiple functions, including postnatal brain maturation, regulation of axonal transport and signaling cascades, cellular response to heat shock, and adult neurogenesis.38
Tau can be divided into four regions: an N-terminal region, a proline-rich domain, a microtubule-binding domain (MBD), and a C-terminal region.39 The human tau gene (MAPT) contains 16 exons, and alternative splicing of exons 2, 3, and 10 yields six isoforms (Figure 2).
The tau protein contains 85 potential serine (S), threonine (T), and tyrosine (Y) phosphorylation sites, and under normal conditions, phosphorylation helps to maintain the cytoskeletal structure.40,41 Abnormal phosphorylation of tau is known to contribute to Alzheimer's disease pathology, with approximately 45 specific phosphorylation sites identified in the Alzheimer's disease brain.40,42
Tau is subject to multiple post-translational modifications in addition to phosphorylation, including glycosylation, glycation, truncation, nitration, oxidation, polyamination, ubiquitination, SUMOylation and aggregation.43
Figure 2. Alternative splicing of tau produces isoforms ranging in length from 352 to 441 amino acids. Exons 2 and 3 of the tau gene encode two N terminal inserts (N1 and N2). Absence of exons 2 and 3 gives rise to 0N tau isoforms, the inclusion of exon 2 results in 1N isoforms and inclusion of both exons 2 and 3 produces 2N isoforms. R1–R4 represent the four microtubule-binding domains with R2 being encoded by exon 10. Inclusion of exon 10 results in 4R isoforms, whilst exclusion results in 3R isoforms.
Accumulation of plaques and intracellular NFTs (Figure 3) is correlated with Alzheimer's disease symptoms and results in neuron damage and death.44 It is now believed that soluble Aβ and tau work in tandem, independently of their accumulation into plaques and tangles, to push neurons towards a diseased state.44
Figure 3. Formation of neurofibrillary tangles (NFTs) by the tau protein in tauopathies such as Alzheimer’s disease. Under pathological conditions, tau becomes hyperphosphorylated and detaches from microtubules. Phosphorylated tau then aggregates to form paired helical filaments (PHFs) and neurofibrillary tangles (NFTs).
In Alzheimer’s disease, the elevation of intracellular soluble Aβ leads to the abnormal phosphorylation of tau and its release from microtubules in a soluble monomeric form.40,45 In response to Aβ, tau is relocated from axons to the somatodendritic compartments of neurons.45 Here, tau can bind and sequester the Src tyrosine kinase, fyn, altering its localization.46
Elevated levels of fyn accompany the elevated levels of tau in dendritic spines, allowing the phosphorylation and stabilization of excitatory GluN2B NMDA receptors. This enhances glutamate signaling and causes an intracellular flood of Ca2+, which enhances Aβ toxicity.44,46,47 Calcium-induced excitotoxicity can damage post-synaptic sites and cause mitochondrial Ca2+ overload, membrane depolarization, oxidative stress and apoptotic cell death.41,44,48,49
Extracellular vesicles may be involved in the dissemination of pathological Aβ and tau in a prion-like propagation of Alzheimer's disease plagues and NFTs.50,51
Novel therapeutic strategies for the treatment of Alzheimer's disease may include preventing the Aβ-induced, tau-dependent enhancement of NMDA receptor activity, by reducing dendritic levels of fyn19 or targeting tau directly.52
Study tau from every angle with a comprehensive array of research tools to provide new insights into tau pathology. From aggregation inhibitors to kits and antibodies, find everything you need to untangle tau, in one place.
Total tau detection
Tau is found in soluble form in the normal brain but in Alzheimer's disease, becomes aggregated and insoluble. Easily detect total tau with a bovine serum albumin (BSA) and azide-free antibody, an antibody panel, or an ELISA kit from the table below.
Table 4. Tools to detect total tau.
Total tau antibody
Anti-Tau antibody [TAU-5] - BSA and Azide free
Tau antibody panel
Tau Research Antibody Panel
Human Tau ELISA Kit
Note: Studying insoluble tau can be problematic, consider using detergents such as RIPA and Sarkosyl.53
Tau function is governed by phosphorylation, which becomes dysregulated during pathology, resulting in mislocalization, aggregation, and neuronal death. Effortlessly study all aspects of tau phosphorylation with antibodies against different post-translationally modified sites.
Table 5. Tools to study tau phosphorylation.
Serine 202 and threonine 205
Anti-Tau (phospho S202 + T205) antibody [EPR20390]
Anti-Tau (phospho T231) antibody [EPR2488]
Anti-Tau (phospho S262) antibody
Anti-Tau (phospho S396) antibody [EPR2731]
Anti-Tau (phospho S422) antibody [EPR2866]
Tau aggregation inhibitors
The presence of aggregated tau corresponds with pathology in diseases such as Alzheimer’s. Effectively inhibit the formation of neurofibrillary tangles with a potent tau aggregation inhibitor.
Table 6. Tou inhibitors.
TRx0237 mesylate (LMTX)
Reduces tau pathology and reverses behavioral impairment in mice.54 Active in vitro and in vivo.55
Selective GSK-3 inhibitor (IC50 = 68 nM) of tau phosphorylation at the S396 site.56
ATP-competitive Dyrk1A inhibitor capable of reversing tau phosphorylation.57
GSK-3β Inhibitor VII
Cell-permeable, non-ATP competitive GSK-3β inhibitor (IC50 = 0.5 µM).58
Allosteric Hsp70 modulator which potently reduces aberrant tau levels (EC50 ~ 0.9 μM).59
Tau and neuroinflammation
There is a complex interplay between misfolded proteins and neuroinflammation in neurodegenerative disease.
Table 7. Tools to study tau in the context of neuroinflammation.
Mouse and human multiplex cytokine panels
Human Key cytokines (15 plex) Multiplex Immunoassay Kit
Mouse Key cytokines (14 plex) Multiplex Immunoassay Kit
TNF alpha ELISA kit
Mouse TNF alpha ELISA Kit
IL-1 beta ELISA kit
Mouse IL-1 beta ELISA Kit (Interleukin-1 beta)
IL-6 ELISA kit
Human IL-6 ELISA Kit (Interleukin-6) High Sensitivity
1. Alzeimer’s Research UK. Dementia Statistics Hub - Global Prevelance. Available at: https://www.dementiastatistics.org/statistics/global-prevalence/.
2. Allinson, T. M. J., Parkin, E. T., Turner, A. J. & Hooper, N. M. ADAMs Family Members As Amyloid Precursor Protein α-Secretases. Journal of Neuroscience Research (2003). doi:10.1002/jnr.10737
3. Haass, C., Kaether, C., Thinakaran, G. & Sisodia, S. Trafficking and proteolytic processing of APP. Cold Spring Harb. Perspect. Med. (2012). doi:10.1101/cshperspect.a006270
4. Hussain, I. et al. Identification of a novel aspartic protease (Asp 2) as β-secretase. Mol. Cell. Neurosci. (1999). doi:10.1006/mcne.1999.0811
5. Sinha, S. et al. Purification and cloning of amyloid precursor protein β-secretase from human brain. Nature (1999). doi:10.1038/990114
6. Vassar, R. et al. β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science (80-. ). (1999). doi:10.1126/science.286.5440.735
7. Francis, R. et al. aph-1 and pen-2 are required for Notch pathway signaling, γ-secretase cleavage of βAPP, and presenilin protein accumulation. Dev. Cell (2002). doi:10.1016/S1534-5807(02)00189-2
8. Levitan, D. et al. PS1 N- and C-terminal fragments form a complex that functions in APP processing and Notch signaling. Proc. Natl. Acad. Sci. (2001). doi:10.1073/pnas.211321898
9. Steiner, H. et al. PEN-2 is an integral component of the γ-secretase complex required for coordinated expression of presenilin and nicastrin. J. Biol. Chem. (2002). doi:10.1074/jbc.C200469200
10. Wolfe, M. S. et al. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and γ-secretase activity. Nature (1999). doi:10.1038/19077
11. Yu, G. et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature (2000). doi:10.1038/35024009
12. Ahmed, M. et al. Structural conversion of neurotoxic amyloid-Β 1-42 oligomers to fibrils. Nat. Struct. Mol. Biol. (2010). doi:10.1038/nsmb.1799
13. Mayeux, R. et al. Plasma amyloid β-peptide 1-42 and incipient Alzheimer’s disease. Ann. Neurol. (1999). doi:10.1002/1531-8249(199909)46:3<412::AID-ANA19>3.0.CO;2-A
14. Coppola, J. M. et al. Identification of inhibitors using a cell-based assay for monitoring Golgi-resident protease activity. Anal. Biochem. (2007). doi:10.1016/j.ab.2007.01.013
15. Jeppsson, F. et al. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of alzheimer disease. J. Biol. Chem. (2012). doi:10.1074/jbc.M112.409110
16. Eketjäll, S. et al. AZD3293: A Novel, Orally Active BACE1 Inhibitor with High Potency and Permeability and Markedly Slow Off-Rate Kinetics. J. Alzheimer’s Dis. (2016). doi:10.3233/JAD-150834
17. Kim, H. et al. Neuroprotective effect of loganin against Aβ<inf>25-35</inf>-induced injury via the NF-κB-dependent signaling pathway in PC12 cells. Food Funct. (2015). doi:10.1039/c5fo00055f
18. May, P. C. et al. The Potent BACE1 Inhibitor LY2886721 Elicits Robust Central A Pharmacodynamic Responses in Mice, Dogs, and Humans. J. Neurosci. (2015). doi:10.1523/jneurosci.4129-14.2015
19. Paris, D. et al. The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation. J. Biol. Chem. (2014). doi:10.1074/jbc.M114.608091
20. Yan, R. Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs. Transl. Neurodegener. (2016). doi:10.1186/s40035-016-0061-5
21. Castellani, R. J., Lee, H. G., Zhu, X., Perry, G. & Smith, M. A. Alzheimer disease pathology as a host response. Journal of Neuropathology and Experimental Neurology (2008). doi:10.1097/NEN.0b013e318177eaf4
22. Knopman, D. S. et al. Neuropathology of Cognitively Normal Elderly. J. Neuropathol. Exp. Neurol. (2003). doi:10.1093/jnen/62.11.1087
23. Schütz, A. K. et al. Atomic-resolution three-dimensional structure of amyloid b fibrils bearing the osaka mutation. Angew. Chemie - Int. Ed. (2015). doi:10.1002/anie.201408598
24. Tycko, R. Amyloid Polymorphism: Structural Basis and Neurobiological Relevance. Neuron (2015). doi:10.1016/j.neuron.2015.03.017
25. Xiao, Y. et al. Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer’s disease. Nat. Struct. Mol. Biol. (2015). doi:10.1038/nsmb.2991
26. Hatami, A., Albay, R., Monjazeb, S., Milton, S. & Glabe, C. Monoclonal antibodies against Aβ42 fibrils distinguish multiple aggregation state polymorphisms in vitro and in Alzheimer disease brain. J. Biol. Chem. (2014). doi:10.1074/jbc.M114.594846
27. Lu, J. X. et al. XMolecular structure of β-amyloid fibrils in alzheimer’s disease brain tissue. Cell (2013). doi:10.1016/j.cell.2013.08.035
28. Petkova, A. T. et al. Self-propagating, molecular-level polymorphism in Alzheimer’s β-amyloid fibrils. Science (80-. ). (2005). doi:10.1126/science.1105850
29. Meyer-Luehmann, M. et al. Exogenous induction of cerebral β-amyloidogenesis is governed bf agent and host. Science (80-. ). (2006). doi:10.1126/science.1131864
30. Pensalfini, A. et al. Intracellular amyloid and the neuronal origin of Alzheimer neuritic plaques. Neurobiol. Dis. (2014). doi:10.1016/j.nbd.2014.07.011
31. Kayed, R. et al. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science (80-. ). (2003). doi:10.1126/science.1079469
32. Kayed, R. et al. Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol. Neurodegener. (2007). doi:10.1186/1750-1326-2-18
33. Kayed, R. et al. Annular protofibrils area structurally and functionally distinct type of amyloid oligomer. J. Biol. Chem. (2009). doi:10.1074/jbc.M808591200
34. Kayed, R. et al. Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers. Mol. Neurodegener. (2010). doi:10.1186/1750-1326-5-57
35. Ballatore, C., Lee, V. M.-Y. & Trojanowski, J. Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci. 8, 663–72 (2007).
36. Gu, Y., Oyama, F. & Ihara, Y. τ Is Widely Expressed in Rat Tissues. J. Neurochem. (2002). doi:10.1046/j.1471-4159.1996.67031235.x
37. Trojanowski, J. Q., Schuck, T., Schmidt, M. L. & Lee, V. M. Distribution of tau proteins in the normal human central and peripheral nervous system. J Histochem Cytochem 37, 209–215 (1989).
38. Morris, M., Maeda, S., Vossel, K. & Mucke, L. The Many Faces of Tau. Neuron 70, 410–426 (2011).
39. Mandelkow, E. M. et al. Structure, microtubule interactions, and phosphorylation of tau protein. Ann. N. Y. Acad. Sci. 777, 96–106 (1996).
40. Noble, W., Hanger, D. P., Miller, C. C. J. & Lovestone, S. The importance of tau phosphorylation for neurodegenerative diseases. Front. Neurol. 4, 1–11 (2013).
41. Danysz, W. & Parsons, C. G. Alzheimer’s disease, β-amyloid, glutamate, NMDA receptors and memantine - searching for the connections. Br. J. Pharmacol. 167, 324–352 (2012).
42. Gong, C.-X. & Iqbal, K. Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Curr. Med. Chem. 15, 2321–8 (2008).
43. Martin, L., Latypova, X. & Terro, F. Post-translational modifications of tau protein: Implications for Alzheimer’s disease. Neurochem. Int. 58, 458–471 (2011).
44. Bloom, G. S. Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71, 505–8 (2014).
45. Zempel, H., Thies, E., Mandelkow, E. & Mandelkow, E.-M. Abeta Oligomers Cause Localized Ca2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines. J. Neurosci. 30, 11938–11950 (2010).
46. Haass, C. & Mandelkow, E. Fyn-tau-amyloid: a toxic triad. Cell 142, 356–8 (2010).
47. Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010).
48. Alberdi, E. et al. Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 47, 264–72 (2010).
49. Bieschke, J. et al. Small-molecule conversion of toxic oligomers to nontoxic β-sheet-rich amyloid fibrils. Nat. Chem. Biol. 8, 93–101 (2012).
50. Vingtdeux, V., Sergeant, N. & Buée, L. Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease. Front. Physiol. 3, 229 (2012).
51. Frost, B. & Diamond, M. I. Prion-like mechanisms in neurodegenerative diseases. Nat. Rev. Neurosci. 11, 155–159 (2010).
52. Murray, M. E. et al. Clinicopathologic and 11C-Pittsburgh compound B implications of Thal amyloid phase across the Alzheimer’s disease spectrum. Brain 138, 1370–81 (2015).
53. Forest, S. K., Acker, C. M., D’abramo, C. & Davies, P. Methods for measuring tau pathology in transgenic mouse models. J. Alzheimer’s Dis. (2013). doi:10.3233/JAD-2012-121354
54. Melis, V. et al. Effects of oxidized and reduced forms of methylthioninium in two transgenic mouse tauopathy models. Behav. Pharmacol. (2015). doi:10.1097/FBP.0000000000000133
55. Panza, F. et al. Tau aggregation inhibitors: the future of Alzheimer’s pharmacotherapy? Expert Opin. Pharmacother. (2016). doi:10.1517/14656566.2016.1146686
56. Marsell, R. et al. GSK-3 inhibition by an orally active small molecule increases bone mass in rats. Bone (2012). doi:10.1016/j.bone.2011.11.007
57. Ogawa, Y. et al. Development of a novel selective inhibitor of the Down syndrome-related kinase Dyrk1A. Nat. Commun. (2010). doi:10.1038/ncomms1090
58. Conde, S., Pérez, D. I., Martínez, A., Perez, C. & Moreno, F. J. Thienyl and Phenyl α-Halomethyl Ketones: New Inhibitors of Glycogen Synthase Kinase (GSK-3β) from a Library of Compound Searching. J. Med. Chem. (2003). doi:10.1021/jm034108b
59. Abisambra, J. et al. Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau. Biol. Psychiatry (2013). doi:10.1016/j.biopsych.2013.02.027