Alzheimer’s Disease & The Cat Out of the Bag

On Monday I went to another lecture hosted by the Center for Translational Neuroscience here at MU.  Dr. Agnes Simonyi spoke about her research on a mouse model of Alzheimer’s Disease.

As she opened her talk, Dr. Simonyi discussed the various animal models that are used to study Alzheimer’s.  Especially with this type of disease, it’s important to consider the different capabilities of a potential animal model.  For instance, can the animal display both behavioral and physiological characteristics that are similar to those of humans with the disease in question?

Dr. Simonyi studies the TgCRND8 mouse model of Alzheimer’s and is currently studying its behavioral characteristics.  These mice are genetically modified to express the human gene, APP.  This gene plays a role in the development of amyloid plaques (or aggregated proteins), which are a prominent feature of Alzheimer’s disease.

With several behavioral tests, Dr. Simonyi is studying mouse behavioral traits that are similar to human symptoms of Alzheimer’s disease: disrupted physical activity, anxiety, memory impairments, and difficulties with activities of daily living (or self-help skills).   I found how Dr. Simonyi is assessing activities of daily living to be particularly interesting.

For mice, a common “activity of daily living” would be building nests out of various materials.  To assess this activity in an experimental setting, TgCRND8 mice and wild type (or normal) mice are given a square of bedding material in their home cage.  About 24 hours later, the quality of a nest built out of the material is rated alongside a measure of how much of the material is torn up.  Preliminary results indicate that the TgCRND8 mice are impaired in this nest-building activity, as compared to wild type mice.   What’s interesting is how these behavioral deficits are present even before amyloid plaques can be detected in the brains of these mice.

Why is this important? In humans, the onset of behavioral symptoms of Alzheimer’s can trail the development of brain damage by as much as 30 years. As my advisor puts it: once you start to see behavioral symptoms of Alzheimer’s, the cat’s already out of the bag.  If signs of memory impairment and other Alzheimer’s symptoms manifest only after a significant progression of the disease, it may be difficult to provide adequate treatment.

What Dr. Simonyi may be on to is an animal model that shows behavioral impairments before it’s too late.   If we can learn more about how Alzheimer’s develops before irreversible changes in the brain occur, maybe we can find a way to keep the cat in the bag.


Tuesday Thoughts: Immune Function in Autism and (of course) Heterogeneity

Example of an antibody

Last week, Dr. Judy Van de Water of UC-Davis gave a talk about current research on immune system dysregulation in autism at the Thompson Center here at MU.  This talk came at an opportune time, as many debates have spurred from some recently published reviews on this topic.   Dr. Van de Water presented some exciting findings, but, refreshingly, remained hesitant to overgeneralize their implications.

Throughout her talk, Dr. Van de Water illustrated potential relationships between the immune system and the development of autism.  For instance, out of the hundreds of gene variants thought to be associated with autism, many are related to immune function.  Also, studies have found alterations in the expression of these genes, as well as abnormal activation of immune-related brain cells and altered brain and cerebrospinal fluid levels of cytokines (immune-related signaling molecules), in autism.

Dr. Van de Water emphasized, though, that the data behind these findings represent the mean (or average) of individuals with autism, not the majority.  These findings do not reflect the inherent heterogeneity (or variability) of immune function in autism.  Dr. Van de Water expressed that while some individuals with autism may have a hyperactive immune system, others may have immune system deficits, and still others may have completely normal immune function.

Additionally, Dr. Van de Water presented findings related to antibody production and autism.  Antibodies function as the body’s defense system against foreign substances and are upregulated in states of immune system activation.  Some antibodies, called autoantibodies, may fight against the body’s own cells.  In autism it seems there are higher levels of autoantibodies in certain brain regions, such as the cerebellum.  This heightened antibody response in the cerebellum may be related to decreased cognitive abilities.

Lastly, antibodies may be related to the development of autism in utero, as some maternal antibodies can cross the placenta and affect fetal brain development.  Some mothers of children with autism express a specific pattern of these antibodies.  Interestingly, a polymorphism of the immune-related MET gene may lead to these altered patterns of antibody expression, meaning this MET variant may function as a susceptibility gene for autism.

At the end of her talk, Dr. Van de Water described a blog post she was asked to write for the Simons Foundation Autism Research Initiative website in light of the thought-provoking column on autism and immune function published in the New York Times. In her post she emphasizes the heterogeneity of autism, and that “generalizing the findings [related to immune dysregulation] from one subtype or group to another can be dangerous where treatment is concerned.”  As has been demonstrated before, the questions related to the study of autism greatly outnumber the answers.  Instead of overgeneralizing the answers, we need to keep asking the questions.

Tuesday Thoughts: Obesity’s One-Two Punch

This week I went to a lecture hosted by the Center for Translational Neuroscience here at MU.   The speaker, James Sowers, MD, discussed obesity and its role in insulin resistance and cardiovascular (heart) disease.  Clearly, this talk was way out of my field, but I did learn some interesting things.

It’s common knowledge that obesity can lead to diabetes and heart disease; however, the mechanisms underlying this progression are not completely understood.

In his talk, Dr. Sowers presented data suggesting that a sedentary (think couch potato) lifestyle, as part of obesity, leads to changes in the body, especially in the heart and muscles. Over time, the body becomes resistant to insulin, a hormone that promotes the storage of certain compounds in body tissue.  When the body no longer responds to insulin, blood vessels stop working properly and heart disease may develop.  These insulin-related problems can develop even before the onset of diabetes.

Dr. Sowers also discussed another punch obesity can throw via over-nutrition, meaning eating too many foods with high fat and sugar content.  Over-nutrition is not only related to obesity, but also seems to directly influence the development of insulin resistance and heart disease.  Interestingly (or perhaps frighteningly) over-nutrition causes certain biological pathways to go into overdrive, causing the overproduction of cells.  In other words, the cascade of events over-nutrition initiates is very similar to that of cancer.  Let’s be clear, eating at McDonald’s five times a week isn’t going to give you cancer.  What might happen, though, are cancer-like processes that can lead to insulin-resistance, and, thus, heart disease.

Being told that obesity is bad and that it can lead to diabetes, which is also bad, is one thing.  But, now to be told that there are more direct links between obesity and heart disease, ones that are part of a cancer-like signaling pathway, is serious enough to make me listen.  Or, at least serious enough to make it easier for me to walk past the post-lecture cheesecake and cookie tray.

Tuesday Thoughts: Autism, Hurricanes, and Mud

A big theory in autism research involves what is called prenatal stress, or maternal stress.  The idea is that a stressful event, such as a hurricane, experienced during a woman’s pregnancy may lead to an increased risk of her child having autism. Several studies supporting this idea have been published.  For example, one of my advisor’s papers, published in 2005, demonstrated that the experience of stressors during a specific time period during pregnancy (weeks 21 to 32) may be related to an increased risk of autism.  Stressors were assessed via surveys and included events like the death of a spouse or being fired from a job.

Confusingly, however, these results conflict with those of very recent studies.   It seems this idea may not be as simple as originally thought. This past June, a paper was published that did not find an increased risk of autism associated with prenatal stress.  This study examined many of the same stressors experienced by pregnant women as those of the above paper, yet the authors did not find the same results.

Results from another study, presented at the 2012 International Meeting for Autism Research, further complicate this picture.  The study examined the incidence of autism in children of mothers who experienced psychosocial stressors, such as physical abuse, during pregnancy.  The twist is that physical abuse experienced during pregnancy was not associated with an increased risk of autism.  Instead, children of women who experienced fear of their partner or physical or emotional abuse in the years just before giving birth had a higher risk of autism.

Why did two very similar studies produce opposite results? Why does it seem that physical abuse during pregnancy is not associated with autism when abuse beforehand is? Many reasons may lie beneath these conflicting and confusing results.  Potentially, gene variants associated with autism are playing a role alongside prenatal stress in causing this disorder. Or different techniques used to carry out the above studies may have contributed to the differing findings. Otherwise, the reasons are about as clear as mud.  For now, the best we can do is put on our finest analytical goggles, jump into the data, and start sorting through the mud.

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