EGCG, Turmeric, and antiAGE nutrients may hit two “birds” with one stone …

A Common Treatment for
Diabetes and Alzheimer’s
Disease?

“Things are not always as they seem.”

By Will Block

T hus we began an article several years ago on a strange connection that may be less strange than we then thought. We wrote, “Whether you regard that as Truth or merely a truism, you would probably agree that, when we’re dealing with the most complex object in the known universe, it’s hard to know exactly what things are, as opposed to how they seem. The object in question is, of course, the human brain (and if there are any alien beings tuned in to our scribblings here on Earth, they’re probably having a horselaugh at our high opinion of our own brains, and our pitiful level of comprehension).

Although it’s difficult for our brains to understand themselves, some of our best ones keep trying, and sometimes pieces of the puzzle come together to reveal something new and significant. That was true when Dr. Suzanne de la Monte, a neuropathologist at Rhode Island Hospital and a professor of pathology at Brown Medical School in Providence, proposed a provocative theory in 2005. Based on a review of the literature and her own research, she and her colleagues suggested that Alzheimer’s disease may actually be a distinct type of diabetes, which they dubbed type 3 diabetes.1,2

AD is a Neuroendocrine Disorder, as is Type 2 Diabetes

In the years between Dr. de la Monte’s 2005 study and now, there has been little additional research on type 3 diabetes, aside from that of de la Monte who has continued to explore the thesis that AD and diabetes are inextricably connected. What she and her team hypothesized, in part, is that AD is a neuroendocrine disorder, as is clearly the case with type 2 diabetes. Insulin functions by controlling neurotransmitter release at the synapses (and the processes involved in this) while activating signaling pathways that are associated with learning and long-term memory. Dr. de la Monte’s research demonstrates that impaired insulin signaling may be implicated in AD.


Dr. de la Monte’s research
demonstrates that impaired insulin
signaling may be implicated in AD.


In post-mortem brain studies, Dr. de la Monte has shown that insulin expression is inversely proportional to the Braak stage of AD progression, when tau tangles have begun to form.3 Tau tangles are neurofibrillary tangles, pathological protein aggregates found within neurons in Alzheimer’s disease. The tangles are formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form. Other researchers have shown that neurotoxins called amyloid-beta(Aβ)-derived diffusible ligands (ADDLs) disrupt signal transduction at synapses, making the cell insulin resistant.4 ADDLs are harmful in several ways: they help cause oxidative damage, reduce synaptic plasticity while increasing synapse loss, and cause formation of tau tangles by destabilizing microtubules that are abundant in the central nervous system.

Oxidative Stress Found in Both Diabetes and AD

Also, diabetes and AD have signs of increased oxidative stress in common, including advanced glycation endproducts (AGEs) formation.5 AGEs are “an unavoidable byproduct of eating digestible carbohydrates, cooking food, and maintaining tightly regulated (not so well regulated in diabetes) circulating levels of glucose in the bloodstream as a necessary fuel.” (See “Advanced Glycation End Products (AGEs) and Life Extension” in the June 2007 issue of Life Extension News in this publication’s archives.) AGEs are the result of a chain of chemical reactions after an initial glycation reaction. Some evidence suggests that diabetics have an increased risk for AD because AGEs accumulate in amyloid plaques and neurofibrillary tangles, adding to brain dysfunction.

Is There a Connection Between Type 2 Diabetes and AD?

The news is constantly abuzz with stories about the insulin resistance/prediabetes epidemic. The likely culprits are diet, lack of exercise, overweight, and obesity. At the same time, AD is emerging as growth disease too. Is it possible that there is a causal connection between type 2 diabetes and AD?


Some evidence suggests that
diabetics have an increased risk for
AD because AGEs accumulate in
amyloid plaques and neurofibrillary
tangles causing further damage.


Could there be a direct correlation between sugar imbalance and AD? We know that AD is associated with consistent pathological findings, including neurofibrillary tangles, Aβ deposits, and signs of oxidative stress. Yet no common link among these pathological processes has been identified.

However, novel evidence has demonstrated that impaired insulin signaling may significantly contribute to the pathogenesis of AD, contributing to the idea that it is actually a neuroendocrine disease.2 Neurotoxins called ADDLs (see above) have been implicated as a cause of impaired insulin signaling.3 AGEs, previously mentioned too, are found in higher concentration in both hyperglycemia and AD, contributing to oxidative stress and cell damage. AGEs are known to be further modified to reactive AGEs (RAGEs), which can generate added oxidative injury. Understanding the mechanism of action of this neuroendocrine disorder may shed light on new tools for diagnosing and treating AD and help prevent obese patients with insulin resistance from converting to type 2 diabetes.

New “Brains” on the Case

Leaping forward to the year 2010, another team of “best brains” has put forward an idea that a gene associated with the onset of type 2 diabetes is found also at lower-than-normal levels in people with AD. In other words, there may be a mechanism that can help explain the relationship between type 2 diabetes and the onset and progression of AD.6 Could this be a case of type 3 diabetes redux?

Conducted by a team of researchers at New York’s Mount Sinai School of Medicine and led by Giulio Maria Pasinetti, M.D., Ph.D., Saunder Family Professor in Neurology, and Professor of Psychiatry and Geriatrics and Adult Development, this new research was published in October’s Aging Cell.

Responding to recent evidence indicating that healthy elderly subjects affected by type 2 diabetes are twice as likely to develop AD, the researchers set out to explain what may be involved. Said Dr. Pasinetti, “The relationship between type 2 diabetes and Alzheimer’s disease has been elusive … This new evidence is of extreme interest, especially since approximately 60 percent of Alzheimer’s disease cases have at least one serious medical condition primarily associated with type 2 diabetes.”

First to Connect PGC-1α with Type 2 Diabetes and AD

Using a mouse model in which genetically engineered mice were selected that had AD comparable to humans, the researchers found that a gene known as PPARγ coactivator-1α (PGC-1α)*—a key regulator of glucose currently investigated as a potential therapeutic target for type 2 diabetes—is decreased in Alzheimer’s disease. In their study, the researchers report that PGC-1α decrease may be causally linked to promotion of AD.

How? PGC-1 promotes degradation of a specific enzyme known as β-secretase (or BACE-1 which stands for beta-site APP-cleaving enzyme 1, where APP is amyloid precursor protein). This enzyme is directly involved in the processing and eventual generation of Aβ, an abnormal protein highly linked to AD and brain degeneration.


*Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. Many articles have appeared in Life Enhancement, including “The Antidiabetes Trigger” in the March 2009 issue, and “Importance of PGC-1alpha in Maintaining Skeletal Muscle Function and Integrity” in the January 2008 issue within Durk Pearson & Sandy Shaw’s Life Extension News (Vol. 10 No. 3 dated November 2007).

† β-Secretase (the β-site of Amyloid precusor protein Cleaving Enzyme) is an aspartic-acid protease, found to be important in the pathogenesis of AD, and in the formation of myelin sheaths in peripheral nerve cells.


Lead researcher Dr. Pasinetti stated that “Our research is the first to find that PGC-1α is a common denominator between type 2 diabetes and Alzheimer’s disease. … This discovery will have significant implications for the more than five million Americans affected by Alzheimer’s disease, a number that is expected to skyrocket in the next three decades as the population ages. We look forward to continuing to research this discovery and translate it into the development of novel approaches for disease prevention and treatment.”

What’s Missing?

The Mt. Sinai researchers say they are optimistic that they can find a way to pharmacologically manipulate PGC-1α to prevent BACE-1 accumulation in the brain, thus diminishing the generation of Aβ. They believe that in the near future, additional studies will provide important insights for the formulation of novel treatments and possible preventative strategies in Alzheimer’s disease. However, some of these solutions are already beating on the door.

Enhancing PGC-1α and Inhibiting BACE with Resveratrol

One recent study has found that peonia (Paeonia lactiflora) seed extract (containing resveratrol oligomer along with 8 related compounds) was successful in the inhibition of BACE-1 in vitro.7 There have been no clinical trials to date of which we are aware. In the course of searching for BACE-1 inhibitors in natural products, the ethyl acetate soluble fraction of Smilax rhizoma (the dried rhizomes of Smilax china L.) showed potent inhibitory activity.8 The active compounds were shown to non-competitively inhibit BACE-1. The active compounds were less inhibitory to alpha-secretase and other serine proteases such as chymotrypsin, trypsin, and elastase, suggesting that they were relatively specific inhibitors of BACE-1. As with peonia, there have been no clinical trials to date of which we are aware.

Both peonia and Similax have been used principally in Traditional Chinese Medicine, almost always as a component of complex formulations. In this tradition, peonia root is used to reduce fever and pain, and on wounds to stop bleeding and prevent infection, and has been used for its antispasmodic effect as reported in the Japanese pharmacopoeia. Similax rhizomes are commonly used in herbalism to treat certain skin diseases which are caused or aggravated by hormonal imbalance, such as psoriasis and seborrhoeic dermatitis.


The Mt. Sinai team says they are
optimistic that they can find a way to
pharmacologically manipulate
PGC-1α to prevent BACE-1
accumulation in the brain, thus
diminishing the generation of Aβ.


Adding more fuel to possible connections, a new resveratrol dimer, vitisinol E, demonstrated inhibitory activity on BACE-1 in vitro.9 This dimer was isolated from a stembark extract of Vitis vinifera together with four known resveratrol oligomers. All isolated resveratrol derivatives demonstrated significant inhibition on baculovirus-expressed BACE-1 in a dose-dependent manner. So it would seem that resveratrol is definitely involved and we know clearly that resveratrol increases expression of PGC-1α.


These two compounds have
novel effects that may be beneficial
for Alzheimer’s disease treatment and,
by extension, type 2 diabetes.


Also, a new isoflavone, neocorylin was isolated from the seeds extract of Psoralea corylifolia L. together with eight known constituents.10 Neocorylin as well as related compounds exhibited a significant inhibitory effect on baculovirus-expressed BACE-1 in vitro. To date, there have been no clinical trials of which we are aware.

Enhancing PGC-1α and Inhibiting BACE with Curcumin and EGCG

BACE-1 is a rate-limiting enzyme for the production of Aβ, which in turn induces the production of radical oxygen species that injure neurons. Oxidative stress plays a key role in various neurological diseases such as ischemia and AD. Recent studies suggest that oxidative stress induces BACE-1 protein upregulation in neuronal cells. In one new study, researchers demonstrated that naturally occurring compounds (-)-epigallocatechin-3-gallate (EGCG) and curcumin suppress Aβ-induced BACE-1 upregulation.11 Exposure of Aβ 1-42 to a neuronal culture increased BACE-1 protein levels. EGCG or curcumin significantly attenuated Aβ-induced radical oxygen species production and beta-sheet structure formation. These two compounds have novel pharmacological effects that may be beneficial for AD treatment and by extension, type 2 diabetes.

Anti-AGE Supplements May Help Both Diabetes and AD

It has been extensively reported that diabetes patients have a higher risk of developing AD, but a mechanistic connection between both pathologies has not been provided so far. Advanced glycation endproducts (AGEs)* have been implicated in the chronic complications of diabetes and have been reported to play an important role in the pathogenesis of AD.12 The earliest measurable manifestation of AD is the appearance of extracellular aggregates of the Aβ peptide. To investigate possible correlations between AGEs and Aβ aggregates with both pathologies, the researchers performed an immunohistochemical study in human post-mortem samples of AD, AD with diabetes (ADD), diabetic, and non-demented controls. ADD brains showed increased number of Aβ dense plaques and receptors for AGEs (RAGE)-positive and tau-positive cells, higher AGEs levels and major microglial activation, compared to the AD brain. The study’s results indicate that ADD patients present a significant increase of cell damage through a RAGE-dependent mechanism, suggesting that AGEs may promote the generation of an oxidative stress vicious cycle, which can explain the severe progression of patients with both pathologies.


* AGEs are the result of a chain of chemical reactions after an initial glycation reaction, in which two molecules, one a sugar and the other a fat or protein are “cooked” and bond, without the control action of an enzyme. Side products generated in intermediate steps may be oxidizing agents (such as hydrogen peroxide), or not (such as Aβ proteins). The term “glycosylation” is sometimes used for “glycation” in the literature, usually as “non-enzymatic glycosylation.”


Fighting AGEs and BACE-1

As readers of this publication already know, there are a number of nutrients that can successfully fight AGEs (see “Reducing Glycation Reactions for Better Health and Longer Life” in the February 2008 issue). These include benfotiamine, carnosine, histidine, alpha-lipoic acid, rutin, thiamine, and pyridoxine. Also, it would appear from what we already know, EGCG and curcumin (or turmeric) can be valuable for resistance/prediabetes and diabetes, along with neurodegenerative disease from mild cognitive impairment to dementias (including AD). EGCG and curcumin (or turmeric) can also inhibit BACE-1 and reduce Aβ-induced radical oxygen species damage and the formation of beta-sheet structure, which is hospitable to protein aggregates and fibrils observed in many human diseases, notably the amyloidoses such as AD. If it turns out that there is such a thing as type 3 diabetes—or even if there isn’t such a disease—those who are concerned with the slippery slope that may take many of us into full-fledged diabetes or all-out AD (or both) will probably find no better place to start their personal defense than with the nutrients named in this paragraph.

References

  1. de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer’s disease. J Alzheimer’s Dis 2005;7:45-61.
  2. Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, Xu XJ, Wands, JR, de la Monte SM. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimer’s Dis 2005;7:63-80.
  3. Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 2006 Mar;9(1):13-33.
  4. De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA 2009 Feb 10;106(6):1971-6.
  5. Valente T, Gella A, Fernàndez-Busquets X, Unzeta M, Durany N. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis 2010 Jan;37(1):67-76.
  6. Gong B, Chen F, Pan Y, Arrieta-Cruz I, Yoshida Y, Haroutunian V, Pasinetti GM. SCF(Fbx2) -E3-ligase-mediated degradation of BACE1 attenuates Alzheimer’s disease amyloidosis and improves synaptic function. Aging Cell 2010 Sep 20. doi: 10.1111/j.1474-9726.2010.00632.x. [Epub ahead of print]
  7. Choi CW, Choi YH, Cha MR, Kim YS, Yon GH, Hong KS, Park WK, Kim YH, Ryu SY. In Vitro BACE-1 Inhibitory Activity of Resveratrol Oligomers from the Seed Extract of Paeonia lactiflora. Planta Med 2010 Oct 1. [Epub ahead of print]
  8. Jeon SY, Kwon SH, Seong YH, Bae K, Hur JM, Lee YY, Suh DY, Song KS. Beta-secretase (BACE1)-inhibiting stilbenoids from Smilax Rhizoma. Phytomedicine 2007 Jun;14(6):403-8.
  9. Choi YH, Yoo MY, Choi CW, Cha MR, Yon GH, Kwon DY, Kim YS, Park WK, Ryu SY. A new specific BACE-1 inhibitor from the stembark extract of Vitis vinifera. Planta Med 2009 Apr;75(5):537-40.
  10. Choi YH, Yon GH, Hong KS, Yoo DS, Choi CW, Park WK, Kong JY, Kim YS, Ryu SY. In vitro BACE-1 inhibitory phenolic components from the seeds of Psoralea corylifolia. Planta Med 2008 Sep;74(11):1405-8.
  11. Shimmyo Y, Kihara T, Akaike A, Niidome T, Sugimoto H. Epigallocatechin-3-gallate and curcumin suppress amyloid beta-induced beta-site APP cleaving enzyme-1 upregulation. Neuroreport 2008 Aug 27;19(13):1329-33.
  12. Valente T, Gella A, Fernàndez-Busquets X, Unzeta M, Durany N. Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer’s disease and diabetes mellitus. Neurobiol Dis 2010 Jan;37(1):67-76.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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