Cobbers on the Brain

Autism affects 1 in 68 people, according to the CDC’s autism monitoring network. Chances are that you probably know someone with Autism, and have seen its effects firsthand.  Autism has been called a uniquely human disorder, as in it may be one of the only disorders that is solely found in humans. For me, this brought up the question: are there animals that have autism? And if not, then why is it just humans that we see the disorder in? 

Scientists went looking for any animals that might display some of the behavioral characteristics that are typical of Autism Spectrum Disorder (ASD) individuals. The problem with this is, how do you know if you’ve found autism? Autism can unfortunately still be somewhat difficult to diagnose from a very young age, and so if we as humans have issues diagnosing it within ourselves, it could be even more difficult to actually pin down when observing an animal. 

Researchers also specifically looked at several different species such as dogs, cats, and monkeys, which have more similarities with humans than some animals would. Although most of the animals they looked at had inconclusive symptoms, they did discover similarities in a breed of dog called Bull Terriers, which they found to display some of the (dog equivalent) behaviors that can be diagnosed as autism in humans. I say “dog equivalent” because some of the staple behaviors of ASD are very difficult to distinguish in animals that can’t talk, such as imparied social interaction and not being able to communicate properly, which in humans can manifest as an inability to formulate speech or something similar. 

These Bull Terriers were found to avoid other people and dogs at a rate that was higher than most other breeds. Another common behavior found in autism is performing repetitive or ritualistic behaviors, and these dogs would also chase their tails for an abnormal amount of time. I know this sounds strange, as in, “so what, the dog is just chasing their tail, they do that”. But if you think about it, if you saw a dog that was chasing its tail for over twenty seconds, (count that out and imagine it if you need to) it stops being cute and playful and starts becoming a little worrisome. These dogs would also have outbursts of anger, another behavior found in autism. This is along with all of these behaviors being found in predominantly male Bull Terriers, which is how also the case with human ASD. 

Now, behaviors by themselves don’t signify autism, so researchers needed some sort of biomarker that they could actually measure to see if physiology of these dogs also matched some of the physiological effects found in humans with ASD. Specifically, they looked at Neurotensin (NT) and Corticotropin-releasing hormone (CRH) levels in Bull Terriers, as they have been found to be elevated in humans with autism. What they found was that the results (levels) in dogs were similar to that of humans, which is an amazing piece of evidence that links up not just the behavioral aspect of autism with animals, but also potentially the physiological side of things too. 

But why does it matter that some Bull Terriers might have the dog-equivalent of autism?

To be able to more effectively learn about, treat, and live with autism (or almost any disorder for that matter), scientists use animal models to be able to figure out things about how these disorders operate. Using animals as test subjects (for the advancement of science), we can further understand how autism might arise genetically, or how to treat its symptoms once it does come about. One of the main goals with treating autism is to try give the individual as normal of a life as they can live, and so using this breed of terrier to try figure that out could improve the lives of countless people with ASD (including the dogs too!). Knowledge is power in the world of science and medicine, so being able to aid with a disorder that has plagued so many would be a worthy achievement.

So first, what exactly is a ganglioside? A ganglioside is a complex lipid that is found in the grey matter of a human brain. These lipids are found to play a major role in brain function, and development, as well as with ‘brain remodeling’ later in a persons life. Seeing as gangliosides are important for brain activity and retention of synaptic plasticity, it only makes sense that an improper regulation of them can cause problems, and it does.

Take for example, in the development of Alzheimer’s, and β amyloid plaques. If the ganglioside GM1 becomes clustered in a plasma membrane microdomain, it can undergo a conformational change and become a binding site for these Aβ oligomers, further promoting aggregation of AβO’s into synaptoxic Aβ plaques. While that is somewhat understood for the ganglioside GM1, an accelerated degradation of the ganglioside GM2 can actually reduce the binding of Aβ on GM1, and is capable of rescuing the cognitive decline caused by GM1 and the Aβ plaques.

Interestingly enough, an unexpected enemy may be at work relating to the modulation of these gangliosides. Diabetes is shown to accelerate the development of these plaques as well as promote the accumulation of the GM1 clusters themselves and in turn, Aβ aggregates. Additionally, there are thoughts that Aβ can be the catalyst behind insulin resistance via interference in the ganglioside metabolism. This interference can cause an increase in GM3 in the plasma membrane, which fits in with another finding that high GM3 results in insulin resistance as well.

For a link between ganglioside regulation and diabetes itself at the surface level, we need to look no further than a dinner plate. A healthy diet we already know is key to not develop diabetes in many people, however it is believed that ganglioside expression in tissues is affected by deficiencies in nutrients, or in foods that do not provide ganglioside synthesis components. For example, breast milk is a very rich source of sialic acid, which happens to be a building block to a major ganglioside in terms of brain development, GM3. Infants who are not breast fed, have a much lower ganglioside content in the frontal cortex of the brain than their breast fed counterparts.

In the end, there is a dualistic relationship between these diseases, and after further research, it is clear the co-morbidity is by no means unrelated. The same plaques that are the hallmark of Alzheimer’s disease have the capability to trigger insulin resistance through both the inhibition of the IR/S to mTOR pathways, as well as via activation of the TNF-alpha receptor which leads to inflammation. On the flip side, as stated above, insulin resistance and diabetes can accelerate the accumulation of GM1 clusters, and in turn the accelerated accumulation of Aβ oligomers into Aβ plaques. The connections between these two diseases are a connection I never had expected to see, and in the future, it’s intriguing to think about how two “unrelated” diseases may be “causes” of each other in the future.

The Link

Alzheimer’s Disease (AD) is the most common form of dementia diagnosed primarily in those older than sixty five and is thought to be caused by the build up of beta amyloid creating plaques and other build ups in the brain that cause neuron degeneration and death. Although this neurodegenerative disease affects over 50 million people world wide, a cure or general treatment has yet to be found. Although, two decades ago, scientists discovered an astounding link between dementia and diabetes. More specifically, between Alzheimer’s disease and type II diabetes. Those who develop type II diabetes will have an insensitivity to insulin which can often times be treated with insulin therapy and recommended exercise, diet change, and medication. The insulin pathway can become disrupted in patients who have Alzheimer’s disease, or those who have an insulin resistance, like in type II diabetes, may develop Alzheimer’s-like symptoms that can turn into actual dementia or AD. Currently, there are four mechanisms that connect Alzheimer’s disease to type II diabetes. This includes TNF-alpha mediated inflammation, unchecked PTP1B activity, deregulated mTOR signaling, and aberrant ganglioside metabolism. Here we will be taking a deeper look into PTP1B and the role it plays in both Alzheimer’s disease and type II diabetes.

The Modulator: PTP1B

It has been recently discovered that protein tyrosine phosphatase 1B (PTP1B) is an important modulator in the insulin pathway as well as in processes in the central nervous system, processes involved in Alzheimer’s disease. In the insulin signaling pathway, PTP1B negatively regulates the insulin pathway by directly affecting the receptor or by affecting down stream substrates (IRS 1/2). It also negatively affects leptin receptors and calcium channels. Over activation of PTP1B is most commonly caused by endoplasmic reticulum stress. Here is where Alzheimer’s disease can play a role in inducing type II diabetes. If a person has AD, there is most likely amyloid plaques present in their brain. These plaques are made up of an over abundance of

amyloid beta oligomers (ABOs). This over abundance can cause ER stress via neuroinflammation. So, ER stress over activates PTP1B which then goes on to over inhibit insulin signaling and receptors, leptin receptors, and calcium channels. If inhibition is present for long enough, a person can develop type II diabetes from the prevalence of insulin insensitivity, but they can also begin to develop worsened AD symptoms including synaptic plasticity and stability impairment and memory and cognition problems.

The steps described above explain how a person with AD can develop type II diabetes as well as progress the symptoms and severity of AD, but similar effects can be seen in a person who initially has insulin insensitivity. In this case, if a person develops type II diabetes from sources other than AD (unhealthy diet, overweight, environmental or genetic factors) and does not get treatment, the lack of insulin signaling can cause cognitive and memory deficits and synaptic plasticity impairment, both of which attribute to the diagnoses of Alzheimer’s disease. Then, if the symptoms become severe enough to where a person develops ABOs, the ER may become stressed increasing activation of PTP1B. No matter if a person is first diagnosed with Alzheimer’s disease or type II diabetes, it does not take much to get wrapped up into the cycle connecting the two diseases.

PTP1B Inhibition: a possible treatment?

Since PTP1B seems to be a problematic common denominator for both Alzheimer’s disease and type II diabetes patients, it seems reasonable to look here for a potential treatment for both diseases, and luckily, scientists are working on this! Inhibiting PTP1B would result in no or less inhibition of insulin signaling, leptin receptors, and calcium channels even under endoplasmic reticulum stress. This would help to decrease the chance of developing type II in AD patients as well as decrease any neurodegenerative symptoms caused by PTP1B caused inhibition. But, it has been deemed an extremely difficult task due to the fact that the active site on PTP1B that an inhibitor would attached to is shared by over 100 other “family members” of this molecule. This makes it difficult for the inhibitor to only effect PTP1B and not any other PTPs present in other parts of the body.

Fortunately, though, when PTP1B inhibitors have been administers peripherally they have been able to cross the blood brain barrier and have effects on the brain. A promising inhibitor that has been going through experimentation is that of CPT157633 and UA0713. In experimental trials these inhibitors have been shown to decrease the amount of PTP1B present in the brain. With continuous effort and research, scientists have the potential ability to create a PTP1B specific inhibitor that could help to alleviate symptoms of AD and type II diabetes or prevent one disease from triggering the other.