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).



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).


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.


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.”

Why Do Some People Get Alzheimer’s Disease but Others Do Not?

Everyone has a brain that has the tools to develop Alzheimer’s disease. Why therefore do some people develop Alzheimer’s disease (AD) while others do not? An estimated five million Americans have AD – a number projected to triple by 2050– the vast majority of people do not and will not develop the devastating neurological condition. What is the difference between those whole develop AD and those who do not?

Subhojit Roy, associate professor in the Departments of Pathology and Neurosciences at the University of California, San Diego School of Medicine, asked this exact question. In a paper published in the journal Neuron, Roy and colleagues offer an explanation for this question. As it turns out, in most people there is a critical separation between a protein and an enzyme that, when combined, trigger the progressive cell degeneration and death characteristic of AD.

“It’s like physically separating gunpowder and match so that the inevitable explosion is avoided,” says principal investigator Roy, a cell biologist and neuropathologist in the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego. “Knowing how the gunpowder and match are separated may give us new insights into possibly stopping the disease.”

Neurologists measure the severity of AD by the loss of functioning neurons. In terms of pathology, there are two tell-tale signs of AD: a) clumps of a protein called beta-amyloid “plaques” that accumulate outside neurons and, b) threads or “tangles” of ‘tau” protein found inside neurons. Most neuroscientists believe AD is caused by the accumulation of aggregates of beta-amyloid protein, which triggers a sequence of events that leads to impaired cell function and death. This so-called “amyloid cascade hypothesis” puts beta-amyloid protein at the center of AD pathology.

Creating beta-amyloid requires the convergence of a protein called amyloid precursor protein (APP) and an enzyme that cleaves APP into smaller toxic fragments called beta-secretase or BACE.

“Both of these proteins are highly expressed in the brain,” says Roy, “and if they were allowed to combine continuously, we would all have AD.”

It sounds inexorable, but it doesn’t always happen. Using cultured hippocampal neurons and tissue from human and mouse brains, Roy and Utpal Das, a postdoctoral fellow in Roy’s lab who was the first author of this paper, and other colleagues, discovered that healthy brain cells largely segregate APP and BACE-1 into distinct compartments as soon as they are manufactured, which ensures that these two proteins do not have much contact with each other.

“Nature seems to have come up with an interesting trick to separate co-conspirators,” says Roy.

What then brings APP and BACE together? Roy and his team found that those conditions that promote greater production of beta-amyloid protein also increase the convergence of APP and BACE. Specifically, an increase in neuronal electrical activity, which is known to increase the production of beta-amyloid, also increased the convergence of APP and BACE. Post-mortem examinations of AD patients have shown that the cellular locations of APP and BACE overlap, which lends credence to the pathophysiological significance of this phenomenon in human disease.

Neurons were cotransfected with APP:GFP and BACE-1:mCherry, neurons were stimulated with glycine or picrotoxin (PTX), and the colocalization of APP and BACE-1 fluorescence was analyzed (see Experimental Procedures for more details). (B) Note that stimulation with glycine greatly increased APP/BACE-1 colocalization in dendrites (overlaid images on right). (C and D) Quantification of APP/BACE-1 colocalization. Note that increases in glycine-induced APP/BACE-1 convergence can
Neurons were cotransfected with APP:GFP and BACE-1:mCherry, neurons were stimulated with glycine or
picrotoxin (PTX), and the colocalization of APP and BACE-1 fluorescence was analyzed (see Experimental Procedures for more details).
(B) Note that stimulation with glycine greatly increased APP/BACE-1 colocalization in dendrites (overlaid images on right).
(C and D) Quantification of APP/BACE-1 colocalization. Note that increases in glycine-induced APP/BACE-1 convergence can

Das says that their findings are fundamentally important because they elucidate some of the earliest molecular events triggering AD and show how a healthy brain naturally avoids them. In clinical terms, they point to a possible new avenue for ultimately treating or even preventing the disease.

“An exciting aspect is that we can perhaps screen for molecules that can physically keep APP and BACE-1 apart,” says Das. “It’s a somewhat unconventional approach.”