Synaptic Regulation of Beta Amyloid Metabolism and Associated Biomarkers in Body Fluids

Mitsuru Shinohara, PhD
Mayo Clinic (Jacksonville, FL)


Guojun Bu, PhD
Washington University (St. Louis, MO)
Year Awarded:
Grant Duration:
July 1, 2014 to November 30, 2016
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Postdoctoral Fellowship
Award Region:
US Southeastern

This grant is made possible in part by a bequest from the Gertrude I. Quoss Trust.

Mitsuru Shinohara, PhD

Synaptic Regulation of Aβ Metabolism and Secreted Markers


To understand why our friends and relatives develop Alzheimer’s disease (its so-called “etiology”), we need to develop biomarkers, or measurable indicators of toxic beta amyloid accumulation in brains. These will help us to evaluate the disease progression as well as the underlying disease processes. Recent studies, including ours, demonstrate that synapses (neuronal connections in brain) play important roles in toxic beta amyloid accumulation. By shedding light on how these synapses regulate the production and behavior of toxic beta amyloid in brains at a molecular level, and what proteins or molecules in body fluids are associated with that process, the results of our proposed research will help identify appropriate biomarkers that indicate disturbances in synaptic beta amyloid metabolism in brains, before the development of Alzheimer’s disease. Such biomarkers would be very useful in order to identify and clarify the triggers underlying Alzheimer’s disease progression and beta amyloid accumulation in individuals, and may ultimately lead to effective treatments for Alzheimer’s disease.


Amyloid-β accumulation in brain is thought to cause Alzheimer’s disease (AD). However, it remains unclear why amyloid-β accumulates in brain. Recent studies by ourselves and others demonstrate that synapses play important roles in amyloid-β accumulation in human brains. To further understand the synaptic involvement in amyloid-β metabolism, we plan to assess synaptic regulation of amyloid-β and other metabolites using novel microdialysis technique and metabolimics approach in animal models.

More Information:
Accumulation and aggregation of amyloid-β peptides proteolytically cleaved from amyloid precursor protein (APP) initiate the pathogenesis of Alzheimer’s disease. While this concept is widely held, it remains unclear why amyloid-β accumulates in the human brain. The pathogenic mechanism of amyloid-β accumulation is apparently heterogeneous; some individuals have amyloid-β accumulation due to the genetic inheritance of mutations in genes that encode for APP and presenilins 1 and 2, or because they have inherited polymorphic allele of apolipoprotein E. However, these genetic variants can only account for fewer than half of total AD cases, thus it remains unclear why of the remaining half of all AD patients had amyloid-β accumulation and eventually developed their condition. Recent studies by ourselves and others demonstrate that synapses play important roles in amyloid-β accumulation in human brains. Our study objective is to reveal the molecular events associated with synaptic regulation of amyloid-β metabolism in animal models by using state-of-the-art techniques.

In the first portion of the study, Dr. Shinohara will assess how synapses regulate APP metabolism leading to amyloid-β production in freely moving animals. To this end, he will use a novel microdialysis technique that can detect large size molecules around 100 kDa (a kDa is a unit of atomic mass signifying one-thousandth of a Dalton, or approximately the mass of one nucleon, either a single proton or neutron). Then he will manipulate synaptic function in pharmacological and non-pharmacological ways in order to determine their effect on APP metabolites.

In the second portion of the study, Dr. Shinohara will assessing how synaptic function affects extracellular metabolites in freely moving animals. In this part of the study will utilize a metabolimics approach that can detect thousands of metabolites at one time. Again the design calls for manipulating synaptic function, similar to that done in the first portion of the study, in order to determine their effects on extracellular metabolites.

Biomarkers, or surrogate markers of disease initiation and progress, would be very useful for helping us understand why people develop Alzheimer’s disease. By studying how synapses regulate APP metabolism and other extracellular metabolites, Dr. Shinohara’s study will identify surrogate biomarkers that indicate disturbances in synaptic Aβ metabolism in brains. Eventually, the results of the study will be useful for tracking and targeting effective treatments for AD.

About the Researcher

Mitsuru Shinohara is a postdoctoral fellow in the laboratory of Guojun Bu, PhD, a neuroscientist at the Mayo Clinic in Jacksonville, FL. Dr. Shinohara’s research into Alzheimer’s disease commenced at the University of Tokyo under the direction of Takeshi Iwatsubo, MD, a neuropathologist, and Taisuke Tomita, PhD, a pathological biochemist. He completed his PhD studies in 2010 at Osaka University under the direction of Ryuichi Morishita, MD, PhD, a cardiologist, and Naoyuki Sato, MD, PhD, a gerontologist. Dr. Shinohara’s major interest lies in studying the etiology and treatments of Alzheimer’s disease. He has been principal investigator or a collaborating scientist in several Alzheimer’s disease research projects, and has been published in over 15 peer-reviewed journals, including the Journal of Biological Chemistry, the Journal of Neuroscience, PNAS, Acta Neuropathologica, and Brain.
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