Natural Compounds as Potential Therapeutic Agents for Inhibiting and Decreasing Tau Protein in Alzheimer’s Disease


The development of Alzheimer’s disease is commonly explained by one of the three hypotheses or all three.  These hypotheses include:  1

  • Cholinergic hypothesis
  • Amyloid beta hypothesis
  • Tau hypothesis

The neurons of the brain consists of a cytoskeleton which acts as an internal support structure.  The cytoskeleton is partly made up of microtubules which are transportation channels that guide nutrients and molecules from the neuron body to the ends of the axon and back again to the neuron body. 

A stablizing protein imbedded into the microtubules is a protein called tau.  Tau is stablized in the microtubule by a process known as phosphorylation.  In the development of Alzheimer’s disease, tau undergoes chemical changes and becomes hyperphosphorylated.  The hyperphosphorylated tau begins to combine with other threads of hyperphosphorylated tau creating neurofibrillary tangles which ultimately disintegrates and collapses the neuron’s transportation system.  2

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Tau in healthy neurons and in tauopathies

Tau facilitates microtubule (MT) stabilization within cells and it is particularly enriched in neurons. MTs serve as “tracks” that are essential for normal trafficking of cellular cargo along the lengthy axonal projections of neurons, and it is thought that tau function is compromised in Alzheimer’s disease and other tauopathies. This probably results both from tau hyperphosphorylation, which reduces the binding of tau to MTs, and through the sequestration of hyperphosphorylated tau into neurofibrillary tangles (NFTs) so that there is less tau to bind MTs. The loss of tau function leads to MT instability and reduced axonal transport, which could contribute to neuropathology.

Source:  Advances in Tau-focused drug discovery for Alzheimer’s disease and related tauopathies

The Tau hypothesis states that the observation of amyloid beta and neurofibrillary tangles lead to the cause of Alzheimer’s disease.

More specifically, the Tau hypothesis proposes that tau protein abnormalities initiate the disease cascade where hyperphosphorylated tau begins to combine with other threads of tau and they eventually form neurofibrillary tangles inside the neuron.  As a result of this process, the microtubules disintegrate which destroys the neuron’s cytoskeleton.  With the destruction of the neuron’s cytoskeleten, the neuron’s transportation system is collapsed. 

When the neuron’s transportation system collapses, a malfunction in the biochemical communication between neuron’s occur.  Ultimately this results in the death of the neuron.  Amyloid beta plaques do not correlate with neuron loss.

The abnormal aggregation of the tau protein defines Alzheimer’s disease as a tauopathy.  Tauopathy is defined as a class of neurodegenerative diseases in which pathological aggregation of tau protein in neurofibrillary or gliofibrillary tangles occur in the human brain.

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The tau hypothesis of Alzheimer’s disease progression

NFT: Neurofibrillary tangles; PHF: Paired helical filaments.

Source:  Advances in Tau-focused drug discovery for Alzheimer’s disease and related tauopathies

A number of therapeutic strategies have been proposed and focuses on targeting the decrease of the microtubule-associated protein tau.  These include:  3

  • controlling tau degradation via chaperones
  • enhance tau clearance
  • inhibiting formation of tau aggregates
  • preventing tau aggregation
  • regulating tau using kinases
  • stabilizing tau microtubules

Scientists have identified a number of natural compounds that have potential in inhibiting or reducing the levels of the tau protein.  The Table below lists some of these identified natural compounds with the abstracts and citation to the various studies:

Natural Compounds as Potential Therapeutic Agents for Inhibiting and Decreasing Tau Protein

Aged garlic (Allium sativum)Current study investigated anti-amyloidogenic, anti-inflammatory and anti-tangle effects of dietary aged garlic extract (AGE) (2%) and compared with its prominent constituents, i.e. S-allyl-cysteine (SAC) (20 mg/kg) and di-allyl-disulfide (DADS) (20 mg/kg) in Alzheimer's Swedish double mutant mouse model (Tg2576).1
Bayberry root bark (Myrica cerifera)The bayberry flavonoids myricetin and myricitrin were confirmed to contribute to this potency, but a diarylheptanoid, myricanol, was the most effective anti-tau component in the extract, with potency approaching the best targeted lead therapies. (+)-aR,11S-Myricanol, isolated from M. cerifera and reported here for the first time as the naturally occurring aglycone, was significantly more potent than commercially available (±)-myricanol. Myricanol may represent a novel scaffold for drug development efforts targeting tau turnover in AD.2
Chinese Yew, Taxus yunnanensisThe stimulatory and inhibitory effects of several compounds and lignans isolated from the water extract of Taxus yunnanensis on the phosphorylation of three functional brain proteins (bovine myelin basic protein (bMBP), recombinant human tau protein (rhTP) and rat collapsin response mediator protein-2 (rCRMP-2)) by glycogen synthase kinase-3β (GSK-3β) were quantitatively compared in vitro3
Cinnamon (Cinnamonium zeylanicum)An aqueous extract of Ceylon cinnamon (C. zeylanicum) is found to inhibit tau aggregation and filament formation, hallmarks of Alzheimer's disease (AD). The extract can also promote complete disassembly of recombinant tau filaments and cause substantial alteration of the morphology of paired-helical filaments isolated from AD brain. Cinnamon extract (CE) was not deleterious to the normal cellular function of tau, namely the assembly of free tubulin into microtubules.4
CurcuminFollowing a six-month prevention period where mice received extract HSS-888 (5mg/mouse/day), tetrahydrocurcumin (THC) or a control through ingestion of customized animal feed pellets (0.1% w/w treatment), HSS-888 significantly reduced brain levels of soluble (~40%) and insoluble (~20%) Aβ as well as phosphorylated Tau protein (~80%).5
Emodin (Japanese Knotweed - Fallopia japonica)Here we demonstrate the feasibility of the approach with several compounds from the family of anthraquinones, including emodin, daunorubicin, adriamycin, and others. They were able to inhibit PHF formation with IC50 values of 1-5 microm and to disassemble preformed PHFs at DC50 values of 2-4 microm. The compounds had a similar activity for PHFs made from different tau isoforms and constructs. The compounds did not interfere with the stabilization of microtubules by tau.6
Fulvic Acid/Humic Acid (Shilajit)Fulvic acid, a humic substance, has several nutraceutical properties with potential activity to protect cognitive impairment. In this work we provide evidence to show that the aggregation process of tau protein, forming paired helical filaments (PHFs) in vitro, is inhibited by fulvic acid affecting the length of fibrils and their morphology. In addition, we investigated whether fulvic acid is capable of disassembling preformed PHFs. We show that the fulvic acid is an active compound against preformed fibrils affecting the whole structure by diminishing length of PHFs and probably acting at the hydrophobic level, as we observed by atomic force techniques. Thus, fulvic acid is likely to provide new insights in the development of potential treatments for Alzheimer's disease using natural products.7
Ginsenoside RdThe result of the present work implied that ginsenoside Rd protected SD rats and cultured cortical neurons against OA-induced toxicity. The possible neuroprotective mechanism may be that ginsenoside Rd decreases OA-induced the hyperphosphorylation of tau by the increase in activities of PP-2A. Thus, this study promises that ginsenoside Rd might be a potential preventive drug candidate for AD and other tau pathology-related neuronal degenerative diseases.8
Grape seed (Vitis vinifera)Recent studies from our laboratory reveal that grape seed-derived polyphenolic extracts (GSPE) potently prevent tau fibrillization into neurotoxic aggregates and therapeutically promote the dissociation of preformed tau aggregates9 10
Green tea (Camellia sinensis)Several phenothiazines (methylene blue, azure A, azure B, and quinacrine mustard), polyphenols (myricetin, epicatechin 5-gallate, gossypetin, and 2,3,4,2',4'-pentahydroxybenzophenone), and the porphyrin ferric dehydroporphyrin IX inhibited tau filament formation with IC(50) values in the low micromolar range as assessed by thioflavin S fluorescence, electron microscopy, and Sarkosyl insolubility.11
MyricetinPolyphenols such as Curcumin, Exifone, and Myricetin exhibit modest inhibition toward fibril formation of tau peptide which is associated with Alzheimer's disease.12
Oleocanthal from olive oil (Oleaeuropaea)Since our unpublished data indicates an inhibitory effect of oleocanthal on Aβ fibrillization, we reasoned that it might inhibit tau fibrillization as well. Herein we demonstrate that oleocanthal abrogates fibrillization of tau by locking tau into the naturally unfolded state.13
Red sage (Salvia miltiorrhiza)The results showed that Tanshinone IIA (tanIIA), protected neurons against the neurotoxicity of Aβ(25-35), increased the viability of neurons, decreased expression of phosphorylated tau in neurons induced by Aβ(25-35), improved the impairment of the cell ultrastructure (such as nuclear condensation and fragmentation, and neurofibril collapse).14
Sage (Salvia offinalis)In this study, we evaluated the effect of a standardized extract from the leaves of sage (Salvia officinalis) and its active ingredient, rosmarinic acid (12), which reduced tau hyperphosphorylation in addition to attenuating several Alzheimer’s disease pathways, such as reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation and amyloid beta accumulation15