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.
Sharoar MG, Shi Q, Ge Y, He W, Hu X, Perry G, Zhu X, Yan R. (2015) Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease. Mol Psychiatry, in press. PMID:26619807
Hu X, Fan Q, Hou H, Yan R. (2015) Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling. J Neurochem, in press. PMID:26465092
Hu X, Hu J, Dai L, Trapp B, Yan R. (2015) Axonal and Schwann cell BACE1 is equally required for remyelination of peripheral nerves. J Neurosci 35(9):3806-14. PMID:25740511; PMCID:PMC4348183
He W, Hu J, Xia Y, Yan R. (2014) β-site amyloid precursor protein cleaving enzyme 1(BACE1) regulates Notch signaling by controlling the cleavage of Jagged 1 (Jag1) and Jagged 2 (Jag2) proteins. J Biol Chem 289(30):20630-7. PMID:24907271; PMCID:PMC4110275
Shi Q, Ge Y, Sharoar MG, He W, Xiang R, Zhang Z, Hu X, Yan R. (2014) Impact of RTN3 deficiency on expression of BACE1 and amyloid deposition. J Neurosci 34(42):13954-62. PMID:25319692; PMCID:PMC4198539
Yan R, Vassar R. (2014) Targeting the β secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol 13(3):319-29. PMID:24556009; PMCID:PMC4086426
Luo X, He W, Hu X, Yan R. (2014) Reversible overexpression of bace1-cleaved neuregulin-1 N-terminal fragment induces schizophrenia-like phenotypes in mice. Biol Psychiatry 76(2):120-7. PMID:24210810; PMCID:PMC3976896
Hu X, He W, Luo X, Tsubota KE, Yan R. (2013) BACE1 regulates hippocampal astrogenesis via the Jagged1-Notch pathway. Cell Rep 4(1):40-9. PMID:23831026; PMCID:PMC3740554
Shi Q, Prior M, Zhou X, Tang X, He W, Hu X, Yan R. (2013) Preventing formation of reticulon 3 immunoreactive dystrophic neurites improves cognitive function in mice. J Neurosci 33(7):3059-66. PMID:23407961; PMCID:PMC3711383
Hu X, Schlanger R, He W, Macklin WB, Yan R. (2013) Reversing hypomyelination in BACE1-null mice with Akt-DD overexpression. FASEB J 27(5):1868-73. PMID:23335052; PMCID:PMC3633823
Deng M, He W, Tan Y, Han H, Hu X, Xia K, Zhang Z, Yan R. (2013) Increased expression of reticulon 3 in neurons leads to reduced axonal transport of β site amyloid precursor protein-cleaving enzyme 1. J Biol Chem 288(42):30236-45. PMID:24005676; PMCID:PMC3798490
Zhou X, Hu X, He W, Tang X, Shi Q, Zhang Z, Yan R. (2011) Interaction between amyloid precursor protein and Nogo receptors regulates amyloid deposition. FASEB J 25(9):3146-56. PMID:21670066; PMCID:PMC3157691
Luo X, Prior M, He W, Hu X, Tang X, Shen W, Yadav S, Kiryu-Seo S, Miller R, Trapp BD, Yan R. (2011) Cleavage of neuregulin-1 by BACE1 or ADAM10 protein produces differential effects on myelination. J Biol Chem 286(27):23967-74. PMID:21576249; PMCID:PMC3129178
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