What is your objective?

In developed nations with aging societies due to longer lifespans, cognitive impairment in the elderly is becoming a big social issue. In Japan, the number of patients with cognitive impairment is said to be about to reach 5 million, with an almost equal number of cases of mild cognitive impairment (called MCI). The most common form of cognitive impairment is Alzheimer's disease. Many aspects of the molecular mechanism of Alzheimer's disease onset are still unexplained and no fundamental cure or drug therapy has been achieved. Since I began biochemical study of the causative factors in Alzheimer's disease in 1990 at New York’s Rockefeller University, I have worked to discover and identify the numerous proteins and genes related to the onset of the disease and have developed early diagnosis methods and identified potential drug targets. At the same time, by discovering the original function of disease-related proteins and genes within neurons, I am engaged in research to establish how aging affects the function of proteins and genes within the body and how this causes the onset of Alzheimer's disease. My aim is thus to be able to say "The end of Alzheimer’s Disease starts with me!" The members of my laboratory are engaged in a very broad range of research, from basic cell biology and biochemistry to clinical sample analysis.

 

What kind of devices do you use for what sort of experiments? 

In order to discover the function of genes in brain and nerve cells, we have created numerous genetically modified mice and are breeding them in sterile environments. We are analyzing the characteristics of Alzheimer's disease in the mouse brain from a biochemical, cell-biological, and pathological point of view, and are working in this way to discover the pathogenic mechanism of the disease.

Figure 1  Sterile room for breeding genetically modified mice Figure 2  Lens tube-less multiplex fluorescent microscope with cooling CCD camera

The primary component of one of the characteristic pathologies of Alzheimer's disease, neuritic or amyloid plaque ("staining" in the brain), is amyloid beta-peptide (Aβ). Neuritic plaques are structures formed when Aβ aggregates and is deposited between neural cells, but it has been discovered that Aβ soluble oligomer displays neurotoxicity prior to deposition. Aβ is created when large amyloid precursor proteins (called APP) are cleaved by proteases. APP is not originally a pathogenic protein, but has the important role in neural cells of connecting the molecular motors that transport substances with the membrane vesicles that contain cargo, a role known as cargo receptor. In order to clarify the role of APP, we culture mouse neural cells and analyze the intracellular transport mechanism under various microscopes. We also use the latest mass spectrometers to analyze samples of patient cerebrospinal fluid and blood provided by medical facilities to investigate the metabolic changes in onset-related factors, and are working thus to develop early diagnosis methods.

Figure 3  Brain slice sample of an Alzheimer's disease model mouse that is developing amyloid plaque (equivalent to a patient's neuritic plaque) Figure 4  Axonal transport of APP membrane vesicles along nerves

 

What's next?

Figure 5  Graduate student conducting research in the laboratory

The new physiologically active substances that we have discovered in our laboratory have been found to protect against the neurological damage characteristic of Alzheimer's disease. At present, we are working to discover the action mechanism and conducting treatment tests on disease model animals. We hope to bring these results to the clinical stage as soon as possible as a step toward developing and making available new therapeutic drugs as a contribution to overcoming Alzheimer's disease.
Also, many of the proteins involved with Alzheimer's disease, like APP, have been reported to be involved in the transport of substances within the nerves. Nerve cells have a complex form with long protrusions, and the failure of intracellular transport systems leads to their death. We are working from a cellular biology perspective to discover what sort of control operates in the transport of substances within nerve cells as part of research that will progress toward discovering the onset mechanism of Alzheimer's disease. Basic biochemical and cellular biological analysis is closely tied to the discovery of disease causes and the development of treatment methods. We want to promote an understanding of this connection among many graduate students and researchers engaged in basic and clinical studies, which will help to build a scientific framework with a wide field of vision.
Research on Alzheimer's disease is a lengthy process. We hope to cultivate many young researchers to carry on and expand this field of research who will go on to play an active role in the world. We also hope that our research work, which trains people in logical thinking, creative thinking, and ability to overcome obstacles, will produce human resources capable of contributing in many other fields as well as in research.