TYPE 2 DIABETES AND ALZHEIMER'S

ONE STONE, TWO BIRDS?

Scientists make a breakthrough in the search for the cure of Alzheimer's

 “In the latter stage of the disease, most of the brain cortex is seriously damaged. The brain shrinks dramatically due to widespread cell death. Individuals lose their ability to communicate, to recognize family and loved ones and to care for themselves.” 

Alzheimer’s disease, a neurodegenerative disease often suffered by the aged has become an ailment needing urgently, a cure or preventive treatment. In 2017, it was recorded that the disease affected 500,000 people worldwide who were below the age of 65 (Alzheimer's Association, 2017).  The disease which was discovered by and named after Dr. Alois Alzheimer in 1906 when he noticed changes in the brain tissue of a woman who died of a rare kind of mental illness  is characterized by brain cell death which begins with the death of neurons and further, the malfunctioning of the synapse (Alzheimer’s association, 2016). A synapse relays information from one neuron to another and neurons are nerve cells carrying information and so in the brains of Alzheimer’s patients, information/signal pathways are blocked. This is indeed deadly because when information fails to leave or get to the brain, every other organ is clueless on what to do and the body begins to fail, literally, because the power house has failed.

What causes this in Alzheimer’s is quite unknown. However, research has shown that people diagnosed with Alzheimer’s often have certain plaques and tangles found in their brains. 

Does the word plaque ring a bell in your mind? 

Awards? 

No.

Imagine instead a mess made from clustered glue or any other sticky substance. 

Got it? 

Okay. 

So plaques like that gather in the brain of an Alzheimer’s sufferer; these plaques are made from Beta Amyloid proteins normally found around neurons. These proteins form clusters and block cell to cell synapsing. 

The tangles on the other hand are easy to imagine. Typically, there’s a means of transportation in the brain; a route for nutrients, oxygen to move through the brain. Certain proteins called tau regulate and ensure that the structure of this transport system is retained and the route for nutrients to pass through is respected. But for Alzheimer’s patients, this Tau protein forgets its job description and breaks down its strands, forming tangles. This leads to a breakdown of the transport system and of course the brain cells being starved of essential nutrients. 

The brain of a patient with latter stage Alzheimer’s is pretty much in a pitiable state with almost no hope to salvage it. And the brain is the worst organ to fail. Remember the day that mechanic told you your car engine had failed? Yeah, Alzheimer’s is basically the same situation indexed to a millionth power.

These discoveries- although they point us towards the cause of this quite dangerous disease- have led us to a T junction where we are unsure which way to go. While drugs which help inhibit Cholinsterase, an enzyme involved in the breakdown of acetylcholine( a chemical messenger useful in learning and memory) are currently being administered to AD patients, there remains no precise cure to combat the underlying disease once and for all. The symptoms are targeted by all available drugs but not the disease itself. A possible reason why is the multifactorial nature of the disease. In Alzheimer’s study, it’s been discovered that not just a single molecule or protein in the brain is responsible for the disease but there are a number of contributing factors. There is no singular explanation for how the disease begins and no specific molecular pathway that triggers it hence drug production is difficult. A breakthrough however was made by some UK and Chinese scientists this year, January precisely, as they discovered what may be the map towards the cure of this ailment.

These scientists, being forearmed with the knowledge that people who have Type 2 diabetes (High blood glucose) generally are at a risk of having Alzheimer’s (Research even says a whooping 70% of them do), sought to apply a novel drug created to fight against Type 2 diabetes in the combat against Alzheimer’s.

If you’re wondering what the link is between Diabetes and Alzheimer’s, quit wondering. I got you.

In 2015, Moran et al performed and published a research on the correlation of Alzheimer’s with Diabetes. They selected 120 aging adults who had Type 2 diabetes and 700 who didn’t. Their cerebrospinal fluids were collected. Basically, a fluid found in the brain and spinal cord. Tests were run on this fluid alongside MRI scans just to measure the amount of Tau and Beta Amyloid and the research showed that the diabetic patients had more of those proteins than the non-diabetic ones.

A further pointer to this relation is the fact that people with type 2 diabetes generally have more insulin in their bodies because of their cells’ resistance to insulin and the body’s attempt to produce more insulin to match the blood sugar level. This high level of insulin has been discovered to pose harm to the brain and may be responsible for the formation of the tangles and plaques. (Sauer, 2016)

That settled. What did the scientists do?

They sought to see the effect of a novel drug called triple receptor agonist (TA) originally discovered for the treatment of diabetes on an Alzheimer’s disease brain. This triple agonist drug is said to be able to activate three different hormone receptors. They include glucagon(GCG), glucagon-like peptide-1(GLP1) and glucose-dependent insulinotropic polypeptide(GDIP) receptors.(Medical Express, 2018)

Hold on. Let’s understand the jargon.

A receptor is generally activated by certain hormones. GCG, GLP1 and GIP are all hormones which have their corresponding receptors. GCG receptor is expressed in the brain, GLP1 and GDIP receptors are activated by the Incretin hormone.  While the job of glucagon is to release blood glucose from the liver, GIP and GLP1 being incretin hormones buffer against the action of glucagon by lowering blood glucose, reducing caloric intake. Hence, this drug with the inherent ability to activate all three receptors proved successful in reversing obesity and correcting diabetes in rodents.(Finan et al, 2015)

This TA which already had acquired a name as a result of its previously attained feat was given to a transgenic mouse model of Alzheimer’s, specifically an APP/PS1 model. 

I got you again. 

What this means is that the mouse used was transduced with human transgenes containing certain mutations on the Amyloid Precursor Protein(APP) gene- Amyloid rings a bell, yeah?- and the presenilin1 (PS1) gene both on chromosomes 21 and 14 respectively. By transgenesis, Alzheimer’s was stimulated in the brain of the mouse and this drug was given to the mice at 10nmol/kg for two months. After which, the results were profound. In the words of JingJing Tai and the other researchers in their 2017 published paper,

  • "The results showed that treatment with TA significantly reversed the memory deficit in the APP/PS1 mice in a spatial water maze test."

  •  "The drug reduced levels of the mitochondrial pro-apoptotic signaling molecule BAX, increased the anti-apoptotic signaling molecule Bcl-2. (Apoptosis= cell death so pro apoptosis basically enhances cell death while anti-apoptosis does the opposite)"

  •  "It further enhanced the levels of BDNF, a key growth factor that protects synaptic function. Levels of synaptophysin were enhanced, demonstrating protection from synaptic loss that is observed in AD."

  • "Furthermore, TA treatment reduced the total amount of β-amyloid, reduced neuro-inflammation and oxidative stress in the cortex and hippocampus."

So there! If a transgenic model of AD seems to have been cured by TA, the very same drug which reversed type 2 diabetes in certain rodents, sufferers of Alzheimer’s and their loved ones seem to have a rejuvenated hope. Although this discovery poses a number of questions like how the delivery of the drug will proceed especially with the hindrance of the blood-brain barrier and also the potential of the drug working in humans since there have been a number of drugs which yielded positive results in mice models but failed in human trials, their lies hope in the novel treatment. 

A potential side effect of the drug is reduced appetite which would normally translate to weight loss as one of the triple agonist hormones GLP-1 has been known to promote satiety and therefore reduce food and water intake. However, this is a small price to pay in the face of the potential victory of obtaining a cure for Alzheimer’s, a disease which claims the lives of its patients within an average of eight years.

For the family and friends of AD sufferers, this is great news. The thought of recovery, of renewed cognitive abilities, of maybe impaired speech being re-enacted is a flicker of light in a really dark place. But let’s not get ahead of ourselves. There’s a time frame of about nineteen years from pre-clinical trial to approval of disease modifying drugs like this. Well, if the result will be positive, it will surely be worth the wait.

 

REFERENCES

Finan, B., Yang, B., Ottaway, N., Smiley, D.L., Ma, T., Clemmensen, C., Chabenne, J., Zhang, L., Habegger, K.M., Fischer, K., Campbell, J.E., Sandoval, D., Seeley, R.J., Bleicher, K., Uhles, S., Riboulet, W., Funk, J., Hertel, C., Belli, S., Sebokova, E., Conde-Knape, K., Konkar, A., Drucker, D.J., Gelfanov, V., Pfluger, P.T., Muller, T.D., Perez-Tilve, D., DiMarchi, R.D., Tschop, M.H., 2015. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21, 27–36.

Moran C, Beare, R, Phan, T.G, Bruce, D.G, Callisaya ,M.L, Srikanth, V, 2015. Type 2 diabetes and Biomarkers of neurodegeneration. American Academy of Neurology.

Tai, J., Liu, W., Li, Y., Li, L., Hölscher, C. 2017. Neuroprotective effects of a triple GLP-1/GIP/glucagon receptor agonist in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Elseivier. 1678, 64-74.

Sauer, A. 2016. How Alzheimer’s could be type 2 diabetes. Alzheimers.net URL: https://www.alzheimers.net/2015-10-14/how-alzheimers-could-be-type-2-diabetes/

Alzheimer’s Association. 2016 Alzheimer’s Disease Facts and Figures. Alzheimer’s & Dementia 2016;12(4) URL: https://www.alz.org/documents_custom/2016-facts-and-figures.pdf

Medical xpress. URL: https://medicalxpress.com/news/2018-01-diabetes-drug-significantly-reverses-memory.html