The following article was written by group member and DS Dad, Richard Mueller. It’s an excellent article and took a lot of patience to put together for your benefit. Excellent job Richard!

 

The role of the two proteins Beta-CTF and Tau in the development of Alzheimer’s

Dear all

Lately there was considerable media coverage on the subject of Alzheimer’s disease and the numerous clinical trials that have failed, despite the zillions spent by Big Pharma in developing new drugs. Now, some in the industry are having second thoughts about their commitment in this field, after Pfizer, one of the biggest forces in drug development recently announced that it was entirely pulling out of neuroscience research. Others are expected to follow suit, which is bad news for us parents eagerly awaiting drugs that eventually will cure this terrible menace for our children with Down Syndrome.

There is growing acknowledgement that scientists may not understand the disease as well as they thought they did. The so-called amyloid hypothesis, stating that the deposition of amyloid β (Aβ) plaques between neurons throughout the brain is the primary cause of Alzheimer’s disease (AD), has been the mainstream concept underlying AD research for over 20 years. Considering the many failed drug trials focussing on inhibition Aβ plaque formation or removal thereof, this theory may quite likely be wrong. This seems to be one of the surprising conclusions drawn from the so-called «Nun Study». «The Nun Study of Aging and Alzheimer’s Disease», is a continuing longitudinal study, begun in 1986, to examine the onset of Alzheimer’s disease in a group of 678 Catholic nuns across the US. The sisters all agreed to open medical and personal records, undergo annual testing and donate their brains after death. One of the nuns, Sister Bernadette, died of a heart attack at 85, never having shown any signs of mental decay, and a subsequent autopsy revealed that her brain was riddled with the plaques and tangles of Alzheimer’s. Latest research suggests that perhaps as many as a quarter of elderly adults who appear cognitively intact are harbouring the pathological criteria for Alzheimer’s.

In accordance with these findings, several studies conducted during the last years have been pointing to other causes, such as the accumulation of a protein called «Beta-CTF» and another protein called «Tau».

Tau pathology, the other big hallmark of Alzheimer’s disease, appears years or decades before Amyloid Beta plaque formation and leads to the massive death of neurons. Interestingly, Taupathology, but not Beta-Amyloid, correlates with disease progression. The more Tau protein tangles, the more severe the level of dementia. Please watch this video clip:

Alzheimer’s Disease: exploring the brain

https://www.youtube.com/watch?v=dj3GGDuu15I

The video clip is already a few years old and some progress has been made concerning the relationship between Amyloid and Taupathology and the sequence leading to dementia.

The role of Beta-CTF in DS neurodegeneration and Alzheimer’s:

Some of you may remember the landmark DS mouse study published in 2006 by Prof. William Mobley, Stanford University. Its results were a first step on the way to what is known today about one of the main reasons for learning disabilities and Alzheimer’s in Down Syndrome. Please read this report:

Gene linked to mental retardation in Down syndrome

https://news.stanford.edu/news/2006/july12/med-downsynd-071206.html

For those who would like to read the study, please refer to this website:

Increased App Expression in a Mouse Model of Down’s Syndrome Disrupts NGF Transport and Causes Cholinergic Neuron Degeneration

https://www.cell.com/neuron/fulltext/S0896-6273(06)00414-4?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0896627306004144%3Fshowall%3Dtrue

Prof. Mobley and his team uncovered the role of APP (Amyloid Precursor Protein), i.e. the transmembrane protein from which Amyloid Beta and Beta-CTF are cleaved. The triple APP gene dosecauses a defect in nerve growth factor transport between neurons which is crucial for learning and memory formation. Deleting one copy of APP significantly increased learning capabilities in mice with Down Syndrome. Prof. Mobley’s study did not specify in which way APP disrupts nerve growth factor transport. But following study which was published three years later nicely proved Beta-CTF, the intraneuronal cleavage product of APP to be the culprit. Beta-CTF is short for «Beta-carboxyl-terminal fragment», and «Intraneuronal cleavage product» means the little snippet of APP which is cleaved inside neurons, unlike Beta-amyloid, which is cut off from APP outside the neuronal cell membrane.

Alzheimer’s-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824382/

The diagram above shows how APP is either cleaved by the enzyme Alpha secretase (right; non-amyloidogenic pathway) or by Beta secretase (left; amyloidogenic pathway). Both cleavage products are subsequently further cleaved by Gamma secretase, producing either a Beta-CTF or C83, both in the intracellular domain of the neuron. To date, of all intracellular APP cleavage products only Beta-CTF has been found to exert a negative effect in Down Syndrome neurons (see W. Mobley’s research)

Factors that detrimentally influence Beta secretase activity, increasing Beta-CTF production are:

oxidative stress
low levels of omega 3 fatty acids.
impaired mitochondrial energy production
– dysfunction of autophagy

Possible Clues for Brain Energy Translation via EndolysosomalTrafficking of APP-CTFs in Alzheimer’s Disease

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215552/

Mitochondrial respiratory inhibition and oxidative stress elevate Beta-secretase (BACE1) proteins and activity in vivo in the rat retina.

https://www.ncbi.nlm.nih.gov/pubmed/17429617

Dysfunction of Autophagy

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748263/

On the other hand, either directly suppressing Beta secretase activity or increasing its benign competitor alpha secretase (which amounts to an indirect suppression of Beta secretase) bring about a reduction of harmful Beta-CTF proteins. Amongst others, following supplements have been shown to promote this desirable effect:

Dysfunction of Autophagy

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748263/

Vitamin E:

Tamagno E. et al, 2002, «Oxidative stress increases expression and activity of BACE in NT2 neurons»

https://www.ncbi.nlm.nih.gov/pubmed/12270690?dopt=Abstract

EGCG and Curcumin:

Shimmyo Y. et al, 2008, « Epigallocatechin-3-gallate and curcumin suppress amyloid beta-induced beta-site APP cleaving enzyme-1 upregulation»

https://www.ncbi.nlm.nih.gov/pubmed/18695518

EC (epicatechin, another catechin found in green tea or in cocoa):

Cox C. et al., 2015, «Dietary (−)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing»

https://www.sciencedirect.com/science/article/pii/S0197458014005016

Omega 3 Fatty Acid DHA:

Lim G. et al, 2005, «A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model» 

http://www.jneurosci.org/content/25/12/3032.long

Vitamins A+D:

Grimm M. et al., 2016, «The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133786/

Grimm M, et al., 2013, «Impact of Vitamin D on amyloid precursor protein processing and amyloid-β peptide degradation in Alzheimer’s disease»

https://www.ncbi.nlm.nih.gov/pubmed/24192346/

Quercetin:

Sabogal-Guaqueta A. et al, 2015, «The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4387064/

Luteolin:

Zheng N. et al, 2015, «Luteolin Reduces BACE1 Expression through NF-κB and through Estrogen Receptor Mediated Pathways in HEK293 and SH-SY5Y Cells»

https://www.ncbi.nlm.nih.gov/pubmed/25589732

Resveratrol:

Choi YH et al., 2009, «A new specific BACE-1 inhibitor from the stem bark extract of Vitis vinifera»

https://www.ncbi.nlm.nih.gov/pubmed/19184970

Magnesium:

​Yu et al., 2010, «Magnesium modulates amyloid-beta protein precursor trafficking and

​processing.»

https://www.ncbi.nlm.nih.gov/pubmed/20413885

Zinc:

​Gough et al., 2011, «Zinc Metalloproteinases and Amyloid Beta-Peptide Metabolism: The

​Positive Side of Proteolysis in Alzheimer’s Disease»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989646/

The role of Tau in Alzheimer’s:

So far, so good, but how about the other disease process called Taupathology?

Japanese scientists, echoing many others around the world, came to following conclusion in a study published in 2018:

«The amyloid (Beta) hypothesis has been the mainstream concept underlying AD research for over 20 years. However, reconsideration of APP and … familial AD indicate that the trigger of AD is closely linked to impairments of APP metabolism and accumulation of APP C-terminal fragments, rather than Aβ production and Aβ amyloid formation. Furthermore, all attempts to develop Aβ-targeting drugs to treat AD have ended in failure and recent findings indicating that the main factor underlying the development and progression of AD is Tau, not Aβ. Therefore, AD is a disorder that is triggered by impairment of APP metabolism, and progresses through Tau pathology, not Betaamyloid. (Kametani et al, 2018: Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer’s Disease https://www.frontiersin.org/articles/10.3389/fnins.2018.00025/full)

A recent study published suggests that Beta-CTF proteins influence Tau proteins. Researchers led by Frederick Livesey at the University of Cambridge, U.K., report that the amount of Beta-CTF correlated with total Tau in human neurons.

(https://www.sciencedirect.com/science/article/pii/S2211124715003599)

As these pathological changes concerning Tau proteins correlate with disease progression in Alzheimer’s long before Beta Amyloid plaques appear on the stage, reducing Tau proteins is paramount. Although Tau plays an important role in normal, healthy neurological activity, when it builds up within neurons early on in the progression of Alzheimer’s disease, it clogs and then kills those cells, as stated in an article at sciencedaily.com (https://www.sciencedaily.com/releases/2018/12/181217115756.htm). To make things worse, Tau proteins have the ability to spread from neuron to neuron, increasing Tau levels and wreaking havoc wherever they go: “The uptake of Tau by neighbouring postsynapses ultimately induces neurofibrillary tangles within downstream neurons via as yet unknown templating or seeding mechanisms. These intracellular inclusions correlate with the cognitive decline and neuronal loss observed in AD”. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5516127)

Beta-CTF proteins are not the only factor contributing Taupathology, there are numerous more, such as neuroinflammation, oxidative stress and mitochondrial dysfunction.

Neuroinflammation causes Tau pathology:

Laurent et al., 2018: «Tau and neuroinflammation: What impact for Alzheimer’s Disease and Tauopathies?»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138617/

Barron et al., 2017: «A state of delirium: Deciphering the effect of inflammation on Tau pathology in Alzheimer’s disease»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479936/

Oxidative stress causes Tau pathology and neuroinflammation:

Huang, et al., 2016 : «Role of oxidative stress in Alzheimer’s disease»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4840676/

Dysfunctional mitochondria contribute to Tau pathology:

Onyango et al, 2018 : «Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer’s disease»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840984/

So, what kind of supplements help in combating Tau pathology?

Following TNI ingredients have been shown to reduce destructive Tau proteins and/or to stop them from aggregating into fibrillary tangles:

Magnesium:

Zhi-Peng et al., 2014: «Magnesium Protects Cognitive Functions and Synaptic Plasticity in Streptozotocin-Induced Sporadic Alzheimer’s Model»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182554/

Selenium:

Van Eersel et al., 2010: «Sodium selenate mitigates Taupathology, neurodegeneration, and functional deficits in Alzheimer’s disease models»

http://www.pnas.org/content/107/31/13888

EGCG (Green Tea Extract):

Branca et al., 2017: «Dyrk1 inhibition improves Alzheimer’s disease‐like pathology»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595697/

Chesser et al., 2016: «Epigallocatechin-3-gallate enhances clearance of phosphorylated Tau in primary neurons»

https://www.ncbi.nlm.nih.gov/pubmed/26207957

Rezai-Zadeh et al., 2008: «Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and modulates Tau pathology in Alzheimer transgenic mice»

https://www.ncbi.nlm.nih.gov/pubmed/18457818

Yin et al., 2017: «Dyrk1A overexpression leads to increase of 3R-Tau expression and cognitive deficits in Ts65Dn Down syndrome mice»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428843/

Guo et al, 2017: «(-)-Epigallocatechin-3-gallate ameliorates memory impairment and rescues the abnormal synaptic protein levels in the frontal cortex and hippocampus in a mouse model of Alzheimer’s disease»

https://www.ncbi.nlm.nih.gov/pubmed/28520620/,

Omega 3 and Curcumin:

Ma et al, 2009: «β-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via c-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3849615/

Vitamin E:

(all tocopherols & tocotrienols, never use only alpha-tocopherol due to increase of Amyloid Beta)

Gugliandolo et al., 2017: «Role of Vitamin E in the Treatment of Alzheimer’s Disease: Evidence from Animal Models»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751107/

Giraldo et al., 2014: «Aβ and Tau toxicities in Alzheimer’s are linked via oxidative stress-induced p38 activation: Protective role of vitamin E»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099506/

Morris et al., 2015: «Brain Tocopherols Related to Alzheimer Disease Neuropathology in Humans»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148466/

Mangialasche et al., 2010: «High plasma levels of vitamin E forms and reduced Alzheimer’s disease risk in advanced age.»

https://www.ncbi.nlm.nih.gov/pubmed/20413888/

Coenzyme Q10:

Elipenahli et al., 2012: «Behavioral Improvement after Chronic Administration of Coenzyme Q10 in P301S Transgenic Mice»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3279177/

Yang et al., 2008: «P2-158: Coenzyme Q10 attenuates hyperphosphorylation of Tau with upregulation of Aktsignaling in the aged transgenic mice with Alzheimer presenilin 1 mutation»

https://aanddjournal.net/article/S1552-5260(08)01392-7/abstract

B-Vitamins:

Nicolia et al., 2010: «B vitamin deficiency promotes Tauphosphorylation through regulation of GSK3beta and PP2A»

https://www.ncbi.nlm.nih.gov/pubmed/20157245

Vitamin A:

Yamada et al, 2012: «Vitamin A and Alzheimer’s disease»

https://www.ncbi.nlm.nih.gov/pubmed/22221326

Vitamin C:

Murakami et al., 2011: «Vitamin C restores behavioural deficits and amyloid-β oligomerization without affecting plaque formation in a mouse model of Alzheimer’s disease»

https://www.ncbi.nlm.nih.gov/pubmed/21558647

Quercetin:

Shen et al, 2018: «Quercetin inhibits okadaic acid-induced Tau protein hyperphosphorylation through the Ca2+calpainp25CDK5 pathway in HT22 cell»

https://www.ncbi.nlm.nih.gov/pubmed/29207020

Resveratrol:

Schweiger et al., 2017: «Resveratrol induces dephosphorylation of Tau by interfering with the MID1-PP2A complex»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5653760/

Selenium:

Van der Jeugd et al., 2018: «Reversal of memory and neuropsychiatric symptoms and reduced Tau pathology by selenium in 3xTg-AD mice»

https://www.nature.com/articles/s41598-018-24741-0

Please read following article. It explains how certain inflammatory molecules called Leukotrienes drive inflammatory processes. Reducing these will help curb neuroinflammation.

Temple Researchers Successfully Reverse Cognitive Impairments in Mice with Dementia (June 2018)

https://medicine.temple.edu/news/temple-researchers-successfully-reverse-cognitive-impairments-mice-dementia

Leukotriene inhibitors:

Curcumin:

Joe et al, 1997: «Effect of curcumin and capsaicin on arachidonic acid metabolism and lysosomal enzyme secretion by rat peritoneal macrophages»

https://www.ncbi.nlm.nih.gov/pubmed/9397403

Houssen et al, 2010: «Natural anti-inflammatory products and leukotriene inhibitors as complementary therapy for bronchial asthma»

https://www.sciencedirect.com/science/article/pii/S0009912010001943

Luteolin and Apigenin:

Kim et al, 2006: «Chemical constituents of the root of Dystaenia takeshimana and their anti-inflammatory activity»

https://www.ncbi.nlm.nih.gov/pubmed/16964755

Quercetin:

Mlcek et al., 2016: «Quercetin and Its Anti-Allergic Immune Response»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273625/

Resveratrol:

Oi et al., 2010: «Resveratrol, a Red Wine Polyphenol, Suppresses Pancreatic Cancer by Inhibiting Leukotriene A4 Hydrolase»

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872628/

And last, but not least, the reduction of brain copper levels, as recommended in the TNI protocol helps to reduce hyperphosphorylated Tau:

Ishihara et al, 2019: «Copper accumulation in the brain causes the elevation of oxidative stress and less anxious behaviour in Ts1Cje mice, a model of Down syndrome»

https://www.ncbi.nlm.nih.gov/pubmed/30660502/

Summary:

Two pathological protein, Tau and Beta-CTF, play a crucial role in the development of Alzheimer’s disease. But only Tau pathology correlates with disease progression, making the prevention of Tau accumulation and phosphorylation to one of the most important measures in combating Alzheimer’s. At least 15 ingredients contained in the current TNI protocol have been shown to have either anti Beta-CTF or anti Tau properties.

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