BACE1 was simultaneously discovered by four groups in 1999. As a co-discoverer of this protein, we have been consistently exploring biological functions and molecular inhibition of BACE1. We have demonstrated that BACE1 deficiency in mice impairs not only developmental myelination but also remyelination following injury. Further biochemical characterization and enzymatic mapping show that BACE1 regulates myelination through cleavage of an important signaling molecule neuregulin-1. We have also shown that BACE1 regulates expression of voltage-gated sodium channel proteins as BACE1 deficiency in mice results in behavioral epileptic seizures. We also study natural factors that may facilitate Aβ production and aggregation in Alzheimer's brains. Recently, we have uncovered Reticulon/Nogo family members as BACE1 modulators. Nogo is best known as a natural factor that inhibits neuritic outgrowth after nerve injury. We found that Nogo and the related protein reticulon-3 (RTN3) interacted with and inhibit the activity of BACE1 in neurons. This is the first study to link factors related to nerve growth to Alzheimer’s pathogenesis. Transgenic mice overexpressing RTN3 and mice deficient in RTN3 are actively used in the lab to determine the role of RTN3 in the control of amyloid deposition and cognitive functions.
We also discovered that RTN3-immunoreactive dystrophic neurites (RIDNs) appear to be the most abundant population of dystrophic neurites in AD. Mice overexpressing RTN3 spontaneously develop RIDNs, and we are exploring a potential causal role of RTN3 in forming RIDNs.
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Although the etiological factors that cause AD remain undefined, genetic studies suggest that excessive production of Aβ, the major component of senile plaques, promotes the onset of AD. Aβ is generated from amyloid precursor protein through sequential cleavages by β-secretase (BACE1) and g-secretase, and our group is one of the first to discover BACE1. Studies have demonstrated that inhibition of BACE1 activity or reduction of BACE1 levels dramatically reduces production of Aβ. Hence, inhibition of BACE1 is a widely pursued for treating AD patients. Our ongoing projects include further investigations of biological functions of BACE1 as well as exploring approaches for molecular inhibition of BACE1. In addition to this line of study, we also investigate the formation of dystrophic neurites, another pathological feature present in association with Aβ deposition in brains of AD patients. We generated an animal model that develop only dystrophic neurites and showed that the presence of dystrophic neurites is highly correlated with learning and memory loss. Further study utilizing this model may decipher molecular formation or inhibition of dystrophic neurites.
Yan R, et al. (1999) Membrane-anchored aspartyl protease with Alzheimer's disease β-secretase activity. Nature 402:533-537.
He W, Lu Y, Qahwash I, Hu X, Chang A, and Yan R. (2004) Reticulon Proteins modulates BACE1 activity and amyloid-β production. Nature Medicine 10:959-965.
Hu, X., Hicks, C.W., He, W., Wong, P., Macklin, W.B., Trapp, B.D., and Yan, R. (2006) Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci., 9:1520-1525.
Hu, X., Shi, Q., He, W., Gearing, M., Levey, A and Yan, R. (2007) Dual functions of RTN3 in formation of amyloid plaque and dystrophic neurites. EMBO.J. 26, 2755-2767.
Shi, Q., Prior, M., He, W., X. Hu and Yan, R. (2009) Reduced amyloid deposition in mice overexpressing RTN3 is adversely affected by preformed dystrophic neurites. Journal of Neuroscience. 29, 9163-9173.