Research

It is well known that extracellular neuritic (senile) plaques and intraneuronal neurofibrillary tangles are two major pathological hallmarks of Alzheimer’s disease (AD). The major component in neuritic plaques is aggregated β-amyloid peptides (Aβ), excised from amyloid precursor protein by sequential cleavages by β- and γ-secretase; the excessive accumulation of these Aβ peptides is widely believed to cause AD.

My group independently co-discovered β-secretase, called BACE1. Inhibition of BACE1 activity or genetic deletion of BACE1 dramatically decreases production of Aβ, implying that BACE1 is an important therapeutic target. The major focus in my laboratory is to investigate biological functions of BACE1 and its regulation.

We have shown that reticulon proteins (RTNs) interact with BACE1 and function as negative modulators of BACE1. We also revealed that BACE1 plays a role in regulating neuregulin signal transduction, which contributes to the hypomyelination of nerves in the central and peripheral systems in BACE1-null mice.

The brains of AD patients often show the presence of dystrophic neurites in addition to plaques and tangles. The presence of dystrophic neurites (also referred to as aberrant neuritic sprouting, swollen dendrites and/or axons) is an important distinguishing feature in AD brains.

We have found that RTN3 plays an important role in the formation of dystrophic neurites. Using biochemical and genetic approaches, we are investigating how RTN3 immunoreactive dystrophic neurites affect AD pathogenesis