For the best experience on the Abcam website please upgrade to a modern browser such as Google Chrome
Take a look at our BETA site and see what we’ve done so far.
Search and browse selected products
Purchase these through your usual distributor
Explore beta-amyloid and tau in Alzheimer's disease and access the tools you need to better understand the role they play within this complex condition.
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.
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 ADAM171. 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 an APP intracellular domain (AICD). To date, the P3 peptide is believed to be pathologically irrelevant2.
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 membrane3–5.
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) 6–10.
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 aggregate11. Elevated plasma levels of Aβ 1–42 have been correlated with Alzheimer’s disease12.
Targeting Aβ accumulation by inhibiting its production is important 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 APP13.
Potent and selective BACE-1 inhibitor (Ki = 26.1 nM), about 14-fold selectivity over BACE-2 (Ki = 372 nM)14.
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)15.
Selective β-secretase inhibitor. Shows neuroprotective effects against Aβ(25-35)-induced cell death16.
Potent and selective BACE-1 inhibitor (IC50 = 20.3 nM for recombinant hBACE-1)17.
Potent Ca2+ channel blocker that promotes Aβ clearance from the brain and reduced tau hyperphosphorylation18.
Selective, potent β-secretase 1 inhibitor (IC50 = 13 nM)19.
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 all20,21.
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 structures22–24.
Therefore, like in prion diseases, unique forms of structurally distinct Aβ might be deposited in different places and at different times in the brains of patients with Alzheimer’s disease. However, it remains unclear which types of deposit are more closely linked with the cognitive symptoms of the disease25.
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 patient26.
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 brain27,28.
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 variation25,29.
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 research30–33.
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 disease34.
The tau protein is highly soluble, expressed in neurons, oligodendrocytes, and astrocytes within the central nervous system (CNS) and peripheral nervous system (PNS)35,36.
Tau 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 neurogenesis37.
Tau can be divided into four regions: an N-terminal region, a proline-rich domain, a microtubule-binding domain (MBD), and a C-terminal region38. 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 structure39. 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 brain39,40.
In addition to phosphorylation, tau undergoes multiple post-translational modifications, including glycosylation, glycation, truncation, nitration, oxidation, polyamination, ubiquitination, SUMOylation and aggregation41.
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, while 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 death42. 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 state42.
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 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 form39,43. In response to Aβ, tau is relocated from axons to the somatodendritic compartments of neurons43. Here, tau can bind and sequester the Src tyrosine kinase, fyn, altering its localization44.
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 toxicity42,44,45. Calcium-induced excitotoxicity can damage post-synaptic sites and cause mitochondrial Ca2+ overload, membrane depolarization, oxidative stress and apoptotic cell death42,46,47.
Extracellular vesicles may be involved in the dissemination of pathological Aβ and tau in a prion-like propagation of Alzheimer's disease plagues and NFTs48,49.
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 fyn18 or targeting tau directly50.
Study tau from every angle with a comprehensive array of research tools to get 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 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
Conformation specific tau antibody
|Anti-tau Alzheimer's disease antibody [GT-38] - Conformation Specific||ab246808|
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.
Rabbit monoclonal to Tau (phospho T217)
Suitable for: Dot blot, ELISA
Reacts with: Human
A carrier-free version of this antibody is also available.
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]
If you need multiple phosphorylated tau antibodies, try our Tau antibody panel (ab226492).
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. Tau inhibitors.
TRx0237 mesylate (LMTX)
Reduces tau pathology and reverses behavioral impairment in mice. Active in vitro and in vivo52.
Selective GSK-3 inhibitor (IC50 = 68 nM) of tau phosphorylation at the S396 site53.
ATP-competitive DYRK1A/B inhibitor capable of reversing tau phosphorylation54.
GSK-3β Inhibitor VII
Cell-permeable, non-ATP competitive GSK-3β inhibitor
Allosteric Hsp70 modulator which potently reduces aberrant tau levels (EC50 ~ 0.9 μM)56.
Browse microtubule activators and inhibitors
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 (17 plex) Multiplex Immunoassay Panel
Mouse Key cytokines (17 plex) Multiplex Immunoassay Panel
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
6. 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. 3:85–97 (2002). doi:10.1016/S1534-5807(02)00189-2
8. 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. 277, 39062–39065 (2002). doi:10.1074/jbc.C200469200
14. Jeppsson, F. et al. Discovery of AZD3839, a potent and selective BACE1 inhibitor clinical candidate for the treatment of Alzheimer’s disease. J. Biol. Chem. 287, 41245–57 (2012). doi:10.1074/jbc.M112.409110
15. 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. 50, 1109–23 (2016). doi:10.3233/JAD-150834
17. May, P. C. et al. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J. Neurosci. 35, 1199–1210 (2015). doi:10.1523/jneurosci.4129-14.2015
25. 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. 289, 32131–32143. (2014). doi:10.1074/jbc.M114.594846
31. 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. 2, 18 (2007). doi:10.1186/1750-1326-2-18
33. Kayed, R. et al. Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers. Mol. Neurodegener. 5, 57 (2010). doi:10.1186/1750-1326-5-57
43. Zempel, H., Thies, E., Mandelkow, E. & Mandelkow, E.-M. Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous tau into dendrites, tau phosphorylation, and destruction of microtubules and spines. J. Neurosci. 30, 11938–11950 (2010).
55. 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. 46, 4631–3 (2003). doi:10.1021/jm034108b
56. Abisambra, J. et al. Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau. Biol. Psychiatry 74: 367–374. (2013). doi:10.1016/j.biopsych.2013.02.027