Building a better future for the brain

RIKEN CBS is also doing work to combat the most serious neurological diseases we face. Alzheimer’s disease is the world’s most common form of dementia, and if we live into very old age, there is a good chance that we will develop it. Japan has the world’s most rapidly aging population, and so any insights from RIKEN CBS that could lead to the development of therapies are a prime example of how we can meaningfully contribute to solving real-world problems.

Using studies on mice, my own lab has discovered a pathway for the activation of dormant stem cells that could generate new neurons to replace those lost due to the disease. However, as writer Anthony King pointed out in Nature in 2018; “Although researchers have conducted more than 400 trials in people of potential treatments for Alzheimer’s disease, almost no drugs have been brought to the market. And despite the blame being placed on a variety of factors, one of the main sources of researchers’ concern is the animal models that are used in the initial stages of drug development.”

Mouse models of amyloidosis don't develop neurofibrillary tangles or neurodegeneration, nor can they reflect most of the cognitive and behavioral changes that affect people with Alzheimer’s disease. Alzheimer’s is also generally considered to be a disease of old age. The mouse models, which are short lived, might therefore reflect only the early stages of the disease. If that is the case, clinical trials of drugs could be failing because people are treated too late to halt brain cell attrition. Could monkeys model the disease more fully? Many think so. Unlike mice, both macaques and marmosets typically develop hyperphosphorylated tau and amyloid plaques as they age. And their amyloid beta sequence is identical to the human protein.

So in the last few years, researchers led by Takaomi Saido at RIKEN CBS and Erika Sasaki at the Central Institute for Experimental Animals, Japan, have created the first nonhuman primate genetic model of Alzheimer’s disease using marmosets.

However, marmosets, which are smaller than macaques, can develop both amyloid beta plaques and hyperphosphorylated tau deposition within seven years, rather than about 25 years for macaques.

Kenya Sato and Hiroki Sasaguri at RIKEN CBS used transcription activator-like effector nucleases (TALEN) to genetically alter the ova of the common marmoset, Callithrix jacchus, deleting a part of a gene found in some people with familial Alzheimer’s disease, exon 9 in the presenilin 1 gene.

The ova were then fertilized with sperm from wild marmosets. Of the six babies that survived until birth, three carried the presenilin 1 mutation. The researchers are hopeful these will develop into a useful model population, as already fibroblasts from the model animals make an increased amount of one of the two major forms for amyloid beta, Aβ42, compared with cells from control animals, which is similar to human presenilin 1 mutation carriers⁸.

RIKEN CBS is also making other brain-disease marmoset models, for Parkinson’s disease and autism, for example.

In Alzheimer’s disease, two key things happen: neurons die more rapidly and stem cells do not produce new neurons as quickly.

Neural stem cells in embryos are very active, but stem cells in adult brains are only occasionally activated and start proliferating, eventually making a small number of new neurons. Formation of new neurons decreases with age, and in Alzheimer’s disease this decrease happens more rapidly and severely.

With my collaborators, I have found that oscillatory expression of the Ascl1 gene plays a critical role in the activation of quiescent neural stem cells and production of new neurons in the adult brain.

We have been studying how gene manipulation and optogenetics can activate aged stem cells for a longer period in model mice and would also like to replicate these studies in marmosets.

But despite the development of primate models, mouse models continue to make important contributions. In 2005, Saido’s group found that the neuropeptide, somatostatin, can increase the neuronal production of the enzyme neprilysin, which can degrade one type of accumulated amyloid beta⁹. Neprilysin production decreases with age, and so activation of the somatostatin pathway may lead to an Alzheimer’s disease therapy.

While there are already many drugs that stimulate the somatostatin pathway, studies of these have been hampered by current Alzheimer’s animal models.

In September 2021, Saido’s group published on a promising new Alzheimer’s disease mouse model¹⁰.

His group had previously developed two mouse models harboring what are known as the Swedish and Beyreuther/Iberian mutations, with or without the Arctic mutation. 

The first model, with the Arctic mutation, exhibited extensive plaque formation in tissue as early as six months, but is unsuitable for investigating amyloid beta metabolism and clearance because the Arctic mutation also renders the amyloid beta resistant to proteolytic degradation. The second model may take as long as 18 months for the pathology to become prominent, which only leaves a short window for study before the end of the mouse’s life.

Saido’s team generated their new model by crossbreeding a model based on a presenilin 1 mutation and their previous model without the Arctic mutation. This new model exhibits early and strong signs of amyloid beta accumulation that isn’t resistant to enzymatic degradation, and the authors say it should be useful for the study of agonists for somatostatin receptor subtypes. The team also has high hopes for studying potential therapies on their new marmoset models.