Brain Cell Regeneration Might Improve Alzheimer’s Disease Symptoms


Adi Shruster and Daniel Offen from Tel Aviv University in Israel have shown in a rodent model of Alzheimer’s disease (AD) that stimulating brain cell regeneration can alleviate some of the symptoms of AD.

A particular mouse strain called 3xTgAD serves as a model system for the study of AD. These mice have several genetic modifications that cause the formation of senile plaques in the brain that also lead to behavioral abnormalities and cognitive decline. In short, the Presenilin gene, which plays a definitive role in the onset of AD, has a mutation engineered in it. This particular mutation (M146V) shows a very strong causative link to inherited forms of AD (MA Riudavets, et al., Brain Pathology 2013 23(5): 595–600).

APP+PS1+Notch

 

Additionally, 3xTgAD mice have a synthetic gene inserted in them that overproduces two proteins that also contribute to the onset of AD: amyloid precursor protein (APP) and another protein called tau. The combination of these three genes causes the formation of amyloid plaques and neurofibrillary tangles that are so characteristic of AD, although these plaques are not exactly the same as those observed in human AD patients (see Matthew J. Winton, et al., Journal of Neuroscience 31(21):7691–7699).

Beta_amyloid

Shruster and Offen used these 3XTgAD mice to determine if inducing new brain cells in the brain could improve their condition. Offen overexpressed a gene called Wnt3a in a part of the brain known to play a role in regulating behavior. Wnt3a is known to drive cell proliferation in this part of the brain. After driving Wnt3a expression in the brains of 3XTgAD mice, Offen subjected them to behavioral tests.

Normal mice tend to pause and assess their surroundings when they enter unfamiliar places. However, 3xTgAD mice tend to charge straight in when entering new surroundings. This lack of proper danger assessment in 3xTgAD mice disappeared when Wnt3a was expressed in their brains. Upon post-mortem examination, these mice showed the formation of new nerve cells in their brains. When new brain cell formation was abrogated with X-rays, the behavioral defect was maintained.

Offen commented: “Until 15 years ago, the common belief was that you were born with a finite number of neurons. You would lose them as you age or as a result of injury or disease.”

Human AD patients can lose their sense of space and reality and do very inappropriate things at particular times. Therefore, these mice do recapitulate particular features of the human disease.

Offen and his colleagues think that establishing the growth of new brain cells in human AD patients might alleviate some of the behavioral abnormalities. Furthermore, stem cell treatments might also have a positive role to play in the treatment of AD, although Offen will readily admit that more work must be done.

Understanding the Role of a Protein in Familial Alzheimer’s Disease


Lawrence Goldstein, director of the UC San Diego Stem Cell Program and a member of the Departments of Cellular and Molecular Medicine and Neurosciences, has an abiding interest in Alzheimer’s disease (AD).  To that end, he and his colleagues have used genetically engineered human induced pluripotent stem cells to determine the role a particular protein plays in the causation of familial AD.  Apparently, a simple loss-of-function model does not contribute to the inherited form of this disorder.  Goldstein hopes that his findings might be able to better explain the mechanisms behind AD and help drug makers design better drugs to treat this disease.

Familial AD is a subset of the larger group of conditions known as early-onset AD.  The vast majority of cases of AD are “sporadic” and do not have a precise known cause, even though age is a primary risk factor (an estimated 5.2 million Americans have AD).  Familial AD is causes by mutations in particular genes.  One of these genes, PS1, encodes a protein called “presenilin 1,” which acts as a protease (an enzyme that clips other proteins in half).  Presenilin 1 is the catalytic component of a protein complex called “gamma-secretase.”  Presenilin 1 forms a complex with three other proteins (Nicastrin, Aph1, Pen2) to form gamma-secretase, and this enzyme attacks specific proteins that are embedded in the cell membrane and clips them into smaller pieces.

gamma-secretase

By clipping these cell membrane proteins into smaller pieces, gamma-secretase helps the cell transport cellular material from one side of the cell membrane to the other side or form the outside of the cell to the inside.

One of the substrates of gamma-secretase is a protein called amyloid precursor protein (APP).  While the function of APP remains unknown, APP cleavage by the gamma-secretase produces small protein fragments known as amyloid beta.

A consensus among AD researchers is that the accumulation of specific forms of amyloid beta causes the formation of the amyloid plaques that kills off neurons and leads to the onset of AD.  The most abundant product of gamma-secretase cleavage of APP is a protein called “Aβ40.”  This protein is forty amino acids long and does not cause any brain damage.  However, a minority product of APP cleave by the gamma-secretase is “Aβ42,” which is 42 amino acids long and forms the amyloid plaques and neurofibillar tangles that are so characteristic of AD (see Scheuner, D., et al., Nat. Med. 2, 864–870).

According to Goldstein, most of the time, gamma-secretase clips APP without causing any problems, but some 20% of the time, the protein clips APP incorrectly and this results in the plaque-forming forms of amyloid beta.  Goldstein explained: “Our research demonstrates very precisely that mutations in PS1 double the frequency of bad cuts.”

To demonstrate this, Goldstein and his co-workers purchased human induced pluripotent stem cells and differentiated them into neurons.  These neurons contained different alleles (forms) of the PS1 gene, and some of these mutant forms of PS1 contained the types of mutations that cause familial AD.  Once PS1 allele in particular called PS1 ΔE9 increased the ratio of Aβ42 to Aβ40 dose-dependent manner.  Since the PS1 ΔE9 causes familial AD, this research elucidates precisely why it does so.

“We were able to investigate exactly how specific mutations and their frequency change the behavior of neurons.  We took finely engineered cells that we knew and understood and then looked how a single mutation causes changed in the molecular scissors and what happened next.”

Presenilin allele consequences

Goldstein further notes, “In some ways, this is a powerful technical demonstration of the promise of stem cells and genomics research in better understanding and ultimately treating AD.  We were able to identify and assign precise limits on how a mutations works in familial AD.  That’s an important step in advancing the science, in finding drugs and treatments that can slow, maybe reverse, the disease’s devastating effects.”