How BACE1 Regulates Learning and Memory Through Molecular Scissors

Ming-Hsuan Ou-Yang, PhD
Northwestern University (Evanston, IL)

Mentors

Robert Vassar, PhD
Northwestern University (Chicago, IL)
Year Awarded:
2015
Grant Duration:
July 1, 2015 to June 30, 2017
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2015289F
Award Type:
Postdoctoral Fellowship
Award Region:
US Midwestern
Ming-Hsuan Ou-Yang, PhD

Paired Ig-Like Receptor B: A Novel BACE1 Substrate

Summary

Beta-secretase 1 (BACE1) is the enzyme that starts the production of the toxic amyloid beta peptide (Aβ) in Alzheimer’s disease (AD). Drugs that block BACE1 to prevent Aβ production are currently being tested in clinical trials as treatments for AD. However, we have discovered that mice lacking the BACE1 gene (BACE1 knockout mice) have impaired memory. Theoretically these mice, because they don’t express BACE1, would seem to model the effects of BACE1 blocking drugs; however, the memory impairment phenotype is opposite that intended for the treatment of AD. As an explanation, we hypothesize that BACE1, acting as a pair of molecular scissors, is important for normal memory by cutting and thus controlling the level of paired-Ig like receptor B (PirB), a molecule that is negative regulator of memory function. This study will test this hypothesis so we can better understand how BACE1 functions and whether there may be potential side effects of future BACE1 drugs, thus devising ways to ensure the safety and effectiveness of such agents.

Details

We are exploring the causal link between paired-Ig like receptor B (PirB), a negative regulator of synapses, and the memory impairments in mice lacking BACE1 (BACE1-/-), the critical enzyme that initiates the production of toxic Aβ in AD. With this approach, we hope to obtain information on the potential side effects that BACE1 inhibitors currently in clinical trials for AD might have on memory.

Based on our preliminary data showing that PirB can be cleaved by BACE1 when co-overexpressed in cultured cells, we hypothesize that brain PirB might also be a substrate of BACE1. Without BACE1 and its cleavage, the level of PirB might be upregulated, thus inhibiting the normal development of synapses and leading to memory deficits in the BACE1-/- mice. To test our hypothesis, we plan to use both mice and cultured cells to investigate whether the level of PirB is regulated by BACE1 cleavage throughout brain development and aging, the nature of this cleavage, and whether PirB is processed by other AD enzymes.

After obtaining this information, in the second part of our study we will attempt to rescue the impaired memory phenotype of BACE1-/- mice by manipulating the level of brain PirB via virus transduction. The rescuing effect will be evaluated by behavioral, electrophysiological, and histopathological analyses on aspects which are known to be compromised in BACE1-/- mice.

This study is highly innovative in three ways: first, the roles of PirB in synaptic plasticity and memory function, and potentially in AD, have only very recently been discovered, making PirB a novel molecule in neuroscience and the AD field. Secondly, our results suggesting that PirB is a novel substrate of BACE1 has never before been reported, and is the first association found between PirB and BACE1. More important, we have correlated deficient processing of PirB by BACE1 to the impaired memory and disrupted synaptic transmission phenotypes found in BACE1-/- mice, the molecular mechanism of which has been unknown to date.

BACE1 inhibitors are currently being tested in clinical trials as treatments for AD. However, the memory deficits in BACE1-/- mice suggest possible mechanism-based side-effects of BACE1 inhibition. By exploring the molecular mechanism underlying the connections between PirB, BACE1, and synaptic plasticity and memory, we hope to provide new insights into how memory is regulated and raise awareness to the possibility of adverse effects, especially related to memory, that might be compromised by therapeutic BACE1 inhibitors in AD patients.

About the Researcher

I was born in Taiwan and grew up there before coming to United State for college. I received my B.S. in biochemistry, summa cum laude from University at Albany, State University of New York. I developed my interests in neurodegenerative diseases, particularly the molecular pathways of disease during my PhD study with William Van Nostrand, PhD, Stony Brook, on the interactions between myelin basic protein and Aβ and amyloid pathogenesis in Alzheimer’s mouse models. In 2014, I joined the lab of Robert Vassar, PhD, at Northwestern University to continue my research on AD by studying the roles of BACE1, another important player in AD with a presence in both the physiological and pathological brain.


"Our brain is such a unique organ that when it’s severely injured, we have a term “brain death” just for it, but we do not have similar terms for other organs. Alzheimer’s disease (AD) is a chronic fatal disease of brain. With AD, people not only lose the capability to perform day-to day-tasks required for independent living, but are also deprived of their memories, a very important part of being human that we use to define who we are. Thus, for me, the ultimate goal of doing AD research is to develop a treatment to maintain the integrity of our life to the end.

Despite the frustrations we have had, I believe with every failure, we are one step closer to the solution. But no great achievement can be made without support from society at large. I give special thanks to the BrightFocus Foundation and its donors for their recognition and generous endowment to science research. Philanthropy has always been a driving force for scientific discoveries, and the generosity of your support will continue to motivate and inspire our research."

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