When combined, omega-3s, turmeric, galantamine, EGCG, and resveratrol make . . .
Cocktails for Alzheimer’s Disease
Pleiotropic nutrients, by their multifaceted nature, can limit Alzheimer’s cascade at all stages without inhibiting normal pathway function
By Will Block
ow many years does it take to develop Alzheimer’s disease (AD), you may wonder? Though there is still much to learn, it is apparent that AD involves a multifaceted pathological cascade which is triggered in the beginning by the accumulation of amyloid-beta (Aβ) peptide aggregates or deviant amyloid precursor protein (APP) processing. Nonetheless, it still takes decades of progression before the onset of cognitive deficits appear—as the neurodegenerative locomotive moves slowly but relentlessly along its tracks toward the impending ravine. If only more were known about the events immediately preceding and precipitating cognitive decline, satisfactory therapeutic strategies to treat and prevent AD would be rapidly developed, and the roadblocks to success would fall.
Thwarting the Pathways of AD Formation
Multiple pathways are thought to play important roles in precipitating cognitive deficits by interfering with the neuronal signals that are instrumental for proper memory function. These pathways are altered by abnormal signaling, oxidative damage, inflammation, and tau* pathology, along with neuron and synapse loss.
It is argued that stage-specific interventions are needed, interventions that not only block causal events in pathogenesis (aberrant tau phosphorylation, Aβ production and accumulation, and oxidative damage), but also address damage from these pathways. Alas, these early symptom (prodromal) pathways are not reversed by targeting associated symptoms. However, it might be better if attention is shifted from the early events in AD formation to measures that correct for loss of synapses. This can be accomplished through the use of substrates for neuroprotective pathways (such as docosahexaenoic acid (DHA), an omega-3 fish oil). Then it is possible that defects in energy metabolism, and adverse consequences of inappropriate compensatory responses (aberrant sprouting) can be thwarted and progress against AD can be made.
Monotherapy, the targeting of early single steps alone in this complicated cascade, may explain disappointments in trials which have used agents that inhibit production, clearance, or the aggregation of the initiating Aβ peptides (or its aggregates). This is especially true when both plaque and tangle pathogenesis have already reached AD levels in the more vulnerable brain regions, during the prodromal period, prior to conversion to mild cognitive impairment (MCI).
Brain Cocktails Limit AD Cascade
Furthermore, in this early stage, many of the pathological events are no longer proceeding in series, but are running in parallel. By the MCI midstage but not later, we stand a greater chance of success by considering pleiotropic drugs or brain cocktails consisting of natural pleiotropic agents. Pleiotropic (Greek pleio, meaning “many,” and trepein, meaning “to turn, to convert”) drugs are those that invoke multiple mechanisms, and provide multiple effects. Some nutrients are pleiotrophic. By their multifaceted nature, pleiotropics may be able to independently limit the parallel steps of the AD cascade at all stages, without completely inhibiting the normal functions of these pathways.
Based on this hypothesis, a recent paper has focused on the pleiotropic activities of omega-3 fatty acids and the anti-inflammatory, antioxidant, and anti-amyloid activity of curcumin (one of the many active compounds found in turmeric) in multiple models that cover many steps of the AD pathogenic cascade. Picking up where the prior paper left off, the recent paper (also authored by the same researchers), argues that genetic data from Down’s syndrome and early-onset AD families increases a 42-amino-acid amyloid-β peptide (Aβ42) that is sufficient to cause clinical onset of AD four to five decades from birth. Bear in mind that genes may not be the only factors to cause this instigation.
Investigations of pathology—more recently though biomarker and imaging studies—show that AD pathogenesis typically begins with nascent Aβ42 aggregates and deposits and related tau accumulation in vulnerable brain regions, for example, medial temporal regions (including the entorhinal cortex, which functions as the hub in a widespread network for memory and navigation, and the hippocampus, which plays important roles in long-term memory and spatial navigation).
Plaques and Tangles Maturity
The early brain-region-specific accumulation of Aβ and tau eventually matures to plaques and tangles. These lead to inflammatory glial cells that emerge in many vulnerable brain regions with distinct differences in the activation pattern for tangles and plaques. After decades of pathology buildup in a prolonged prodromal phase, synapse deficits and neuron loss seemingly play a major role in cognitive decline. Indeed, cross-sectional autopsies have shown that individuals who are apparently cognitively normal often have high levels of plaques and or tangles. This is consistent with the idea that much of the pathology precedes cognitive decline.
During these declines, deficits are associated with spreading tangles, synaptic impairments, and neuron loss. One biomarker has proven to be fairly sensitive to detect amyloid (or its correlates) at pre-MCI stages. This is the ratio of tau to Aβ42, the increase of which in the central spinal fluid can usually predict declines. Along with other observations, the tau/Aβ42 ratio increases support for the idea that amyloid accumulation occurs in the prodromal period preceding clinical onset, followed by a progression of tau pathology and neurodegeneration closely related to cognitive decline. This is also supported by earlier studies showing a close correlation between cognitive decline and synapse loss, but a lesser one with tau or Aβ pathology when considered separately.
Promising Pleiotropic Nutrients
DHA is an omega-3 fatty acid found in marine algae, fatty fish, and fish oil. However, fish may carry the risk of toxic metal contamination such as mercury. While the World Health Organization/Food and Agriculture Organization has determined the tolerable weekly intake of methylmercury to be 80 μg/50 kg body weight per week, fish oil supplements contain 9.89 to 123 ng/g (μg, for microgram, means one-millionth of a gram; ng, for nanogram, means one-billionth of a gram, so 80 μg is 1,000 times larger than 80 ng, and thus fish oil supplement possess only 0.01–0.15 percent of the methylmercury found in fish, a small fraction of 1 percent of the tolerable weekly intake). Therefore, only by using fish oil supplements can one be reasonably sure of staying within the tolerable range—by a wide margin indeed.
Supplemental DHA has been found to lessen AD pathogenesis. Drebrin (a protein thought to play a role in the process of neuronal growth) loss is an early marker of synaptic deficits in MCI, and DHA has been found to protect against drebrin loss in an AD mice model. Two small trials now show that high-dose fish oil supplements appear to slow progression from very early stage AD or MCI. And three larger trials also suggest some efficacy of DHA or fish oil in people, although possibly only beneficial in subjects lacking the apolipoprotein ApoE4 allele (although 40-65% of AD patients have at least one copy of ApoE4, it is not a determinant of the disease).
DHA also appears protective in the epidemiology of dementia and AD, at least in subjects lacking ApoE4, and at many neuroprotective or anti-AD effects of DHA have been reported in preclinical models. DHA’s neuroprotective and other effects in preclinical models include:
- Anti-inflammatory activity. Unlike conventional non-steroidal anti-inflammatory drugs (NSAIDs), DHA can competitively reduce central nervous system levels of arachidonic acid (AA).* Fish oil has been shown to reduce AA and cardiovascular risk in arthritis patients consuming NSAIDs. This AA metabolite reduction extends also to the brain. Omega-3s are known to reduce NSAID requirements in inflammatory conditions, but unlike NSAIDs which may increase cardiovascular risk, omega-3s reduces cardiovascular risk, even in NSAID users.
- Insulin/trophic factor induction of neuroprotective activity is elevated by DHA.
- DHA increases brain-derived neurotrophic factor (BDNF) synthesis. Since BDNF is reduced in AD and is strongly neuroprotective in AD models, this effect may be quite protective.
- Antioxidant effects, in membrane and indirect activity by increasing antioxidant enzymes such as catalase and glutathione peroxidase, important made-in-the-body antioxidants.
- Neuroprotective enzymatic metabolites. DHA metabolites are reported to have anti-apoptotic/anti-inflammatory and other neuroprotective effects, which have been reported to exert multiple anti-apoptotic and other anti-AD activities.
- Promotion of neurogenesis and neurite extension. DHA promotes neurite outgrowth in vitro and neurogenesis and improves cognition in vivo.
- Increases of glucose transportation. While glucose utilization is reduced in AD, DHA increased the expression of a major brain endothelial cell glucose transporter.
- DHA improves the age-impaired coupling of blood flow to glucose utilization in aged monkeys. This may be a factor in both AD and vascular dementia.
- Neuronal and synaptic membrane fluidity and lipid raft function are believed to decline with aging. DHA improves synaptic membrane fluidity when it is esterified to membrane phospholipids. Imaging data suggest that this effect can be seen in humans. DHA also enhances lipid raft function. Lipid rafts are specialized membrane domains enriched in certain lipids, cholesterol, and proteins. Among the functions attributed to rafts are cholesterol transport, endocytosis (the process by which small particle, molecules and liquids are taken into cells), and signal transduction.
- DHA increases G protein coupling. While this effect has been established in the retina, it may also be important in neuroprotection.
- DHA can activate peroxisome proliferator-activated receptor (PPAR) and nuclear retinoid X receptor alpha (RXRalpha), both of which are involved in the regulation of lipid biosynthesis.
- DHA can protect against oligomer-induced synaptic marker loss in primary neurons. One candidate mechanism involves blocking Aβ-induced deterioration of insulin receptor substrates by tau.
- DHA modestly suppressed Aβ production and amyloid accumulation in vitro and in animal models. Fish oil has also been reported to increase the expression of transthyretin, which is an Aβ-clearing transport protein. DHA may also increase levels of insulin-degrading enzyme and Aβ clearance.
- DHA can suppress two important tau kinases that promote tau pathology and neurofibrillary tangles.
The one caveat is that DHA is highly
susceptible to lipid peroxidation, and
a marker for this is elevated in AD.
When taken together, these pleiotropic activities provide multiple pathways for combating AD pathogenesis, first by reducing amyloid (Aβ) production and accumulation, but also multiple ways for suppressing downstream tau kinases and tau pathology, reducing inflammation and oxidative damage, enhancing neuroprotective and neurogenic pathways, and increasing glucose utilization and neuron and synapse function.
What is most remarkable is that all of these beneficial activities occur within a range of dosing with proven safety. The one caveat is that DHA is highly susceptible to lipid peroxidation, and a marker for this is elevated in AD. This implies that the AD brain does not possess sufficient antioxidant protection for DHA. Consequently, it is imperative to combine DHA with protective antioxidants, for example, such as vitamin E, vitamin C (preferably in the fat-soluble form, ascorbyl palmitate), and diosmin, a compound found in rosemary. DHA should also be combined with turmeric (containing curcumin and other active compounds, most of which are polyphenolic antioxidants which possess other potent antiaging, anti-amyloid, and AD protective activities). Combination of curcumin and fish oil in a mouse model expressing AD has shown promising results.
Extracts of curcumin, the yellow pigment found in turmeric root, have been used in both Indian traditional Ayurvedic medicine and traditional Chinese and Southeast Asian medicines. Curcumin has pleiotropic effects with antioxidant, anti-inflammatory, anti-carcinogenic and neuroprotective properties. Among its uses are as an anti-inflammatory agent and for enhanced wound healing in many tissues. But there is much more, including benefits that are relevant to neuroprotection and AD. These include antioxidant, anti-inflammatory, and anti-amyloid activities as well as promotion of neurogenesis, heat shock protein synthesis, limiting tau, and the maintenance of insulin receptor function. The pleiotropic activities of curcumin (and likely, the many other active compounds found in turmeric) that pertain to AD follow:
- Aβ-binding properties: Curcumin has direct anti-amyloid and anti-Aβ oligomer activity in vitro and in vivo. The binding affinity of curcumin for Aβ aggregates is quite high. In principle, curcumin could also bind other β-pleated sheet structures including prion aggregates as well as synuclein* and tau aggregates.
- Tau-binding properties: Curcumin and related polyphenols have been found to act as tau aggregation inhibitors.
- Stimulation of phagocytic Aβ clearance: Much as the amyloid vaccine operates, curcumin appeared to increase the association of phagocytic (cell eating) cells with plaque structures in a rat AD model. These effects may derive from modulation of the state of microglial activation through effects on AA metabolites.
- Anti-inflammatory: Curcumin limits AA substrates and aberrant inflammatory cytokine production. Unlike classical NSAIDs, curcumin does not appear to directly inhibit COX (an enzyme that is responsible for formation of important biological mediators called prostanoids; the inhibition of COX can provide relief from inflammation and pain) but like DHA, it has profound effects on limiting multiple AA metabolites.
- Antioxidant: Unlike ibuprofen, curcumin can effectively protect against oxidative damage in AD. Curcumin is typically used as a food preservative for reason of its antioxidant properties. In fact, it can protect polyunsaturated fatty acids from lipid peroxidation, and thus possibly do the same for highly unsaturated omega-3 fatty acids. The authors of references #1 and #2, Drs. Sally A. Frautschy and Greg M. Cole show (in unpublished data) that a cocktail containing both DHA and bioavailable curcumin can reduce cognitive deficits and tau pathology in human tau mice beginning treatment at 14 months. This is well after tau pathology and cognitive deficits develop.
- Metal chelation: Another important mechanism of curcumin is metal chelation, which requires a certain type of bond, without which, for example, when curcumin is reduced to tetrahydrocurcumin, it loses its impact on reducing plaque, although it retains its ability to reduce Aβ oligomers.
- Neurogenesis: Curcumin may enhance neurogenesis.
Summarizing these above points, curcumin is truly a pleiotropic agent that can be used to treat aberrant and chronic inflammation, along with oxidative damage, amyloid pathology, and tau pathology.
Curcumin Safety and Bioavailability Issues
Fortunately, turmeric (or curcumin, one of its active compounds) does not cause gastrointestinal bleeding as do NSAIDs, or other toxicity issues of conventional NSAIDs such as naproxen and indomethacin, which limit their use. Pleiotropic agents probably achieve their benefits without side effects because they do not relying on targeting a single pathway. AD does not involve a foreign pathogen, but instead the dysregulation of pathways with normal functions. In this way it behaves like many other age-related chronic diseases. The potential targets of turmeric and cumcumin include oxygen radicals, COX and AA metabolites, tau, tau kinases, APP, secretases, and even Aβ. However, all of these targets have normal functions and, when inhibited, can be expected to result in side effects. While specificity is generally believed to promote safety—true when the targets are purely pathogenic—safety may not follow when the targets have normal functions and are dysregulated in some ways but not others. Nevertheless, by partially inhibiting multiple branches of the cascade, it may be possible to achieve substantial efficacy with fewer side effects.
Lastly, while the poor bioavailability of curcumin may limited its utility, its general benevolence can sustain higher levels of consumption. On the other hand, bioavailability, when much higher levels are required, may be mediated by liposome or other microencapsulation delivery systems, such as nanospheres. These are already in clinical trials for cancer as well as Alzheimer’s and other neurodegenerative diseases of aging.
The Many Facets of Galantamine
Galantamine is pleiotropic also, having been found to reduce the release of reactive oxygen species (up to 50%) and prevent loss in mitochondrial activity. Furthermore, it is an acetylcholinesterase inhibitor (AChEI) and also an allosteric potentiating ligand that modulates presynaptic nicotinic acetylcholine receptors. This means that galantamine inhibits the breakdown of acetylcholine molecules and improves the receptivity of neurons to acetylcholine molecules that are trying to transmit nerve impulses across a synaptic junction.
Green Tea’s EGCG
As well, EGCG (epigallocatechin gallate) meets the pleiotropic criteria. In vitro studies demonstrate that green tea extract probably protects neurons from Aβ-induced damages, and that EGCG, a major catechin isolated from the polyphenolic fraction of green tea, reduces Aβ generation while decreasing Aβ levels and plaques in AD mice. EGCG also elevates the activity of enzymes that inhibit generation of APP.
The multiple function of resveratrol may be greater than all the other pleitriopic nutrients combined, including its ability to act as a sirtuin and an mTOR inhibitor (see
“Cardioprotection, Possible Life Extension Inhibitors of mTOR Revisited: Resveratrol” in the April issue of Life Extension News), to name two of its life extending characteristics, at least in lower organisms but including mammals. Resveratrol also possesses antioxidant properties that protect spatial learning and memory deficits from the oxidative effects of ethanol in the hippocampus. This is germane to AD. It also demonstrates estrogen-like activity, which in hormone replacement therapy has been associated with improved memory. Perhaps even more important, resveratrol—along with turmeric, curcumin, and EGCG—reduces the generation of neurotoxic Aβ, along with activating endogenous pro-survival pathways, including genes that help to enhance cellular defense mechanisms, which may protect the brain against Aβ proteins and deposition of plaques.
In the End—A New Beginning?
AD is a complicated syndrome of aging with a decades-long prodromal period during which Aβ accumulation and tau pathology are accompanied by oxidative damage and inflammation, which precede insidious clinical onset. Acting independently or together, these factors can cause neuronal damage and cognitive deficits. When clinical deficits finally manifest, the neurodegenerative disease is already progressing at all stages at the same time in different regions of the brain.
If we are successful in nipping the cascade in the bud, interventions need to be as early as possible by targeting components of the progression, such as Aβ accumulation which usually begins early in disease generation. Later treatment is less likely to be feasible given the decades-long prodromal period. So early intervention with safe and inexpensive pleiotropic agents—including DHA, curcumin (or turmeric, from which it comes), galantamine, EGCG, and resveratrol—is a strong rationale and in a cocktail may even be effective at later stages due to their multifaceted activities.
- Frautschy SA, Cole GM. Why pleiotropic interventions are needed for Alzheimer’s disease. Mol Neurobiol 2010 Jun;41(2-3):392-409.
- Cole GM, Frautschy SA. Commentary on “Cytoskeletal modulators and pleiotropic strategies for Alzheimer drug discovery.” Pleiotropic approaches to Alzheimer’s and other diseases of aging. Alzheimers Dement 2006 Oct;2(4):284-6.
- Ma Q-L, Yang F, Rosario E, et al. Aβ oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via JNK signaling: suppression by omega-3 fatty acids and curcumin. J Neurosci 2009;29:9078–89.
Will Block is the publisher and editorial director of Life Enhancement magazine.