Riqiang Yan, Ph.D.

Staff and Vice Chair
Morris R. and Ruth V. Graham Endowed Chair in Biomedical Research
Professor, Molecular Medicine, CCLCM-CWRU

Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 445-2690
Fax: (216) 444-7927

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.

In other words ...

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.

Brati  Das Ph.D.
Brati Das Ph.D.
Research Fellow

Phone:(216) 445-2691
Fax:(216) 444-7927

Qingyuan  Fan M.D., Ph.D.
Qingyuan Fan M.D., Ph.D.
Research Fellow

Phone:(216) 445-2691
Fax:(216) 444-7927

Manoshi  Gayen PhD
Manoshi Gayen PhD
Research Fellow

Phone:(216) 445-2691
Fax:(216) 444-7927

Yingying  Ge
Yingying Ge
Research Scholar

Phone:(216) 445-2691
Fax:(216) 444-7927

Yinzheng  Guan
Yinzheng Guan
Graduate Student

Phone:(216) 445-2691
Fax:(216) 444-7927

Wanxia  He
Wanxia He
Principal Research Technologist

Phone:(216) 445-2691
Fax:(216) 444-7927

Xiang-You  Hu M.D., Ph.D.
Xiang-You Hu M.D., Ph.D.
Project Staff

Phone:(216) 445-2691
Fax:(216) 444-7927

Md. Golam  Sharoar Ph.D.
Md. Golam Sharoar Ph.D.
Research Associate

Phone:(216) 445-2691
Fax:(216) 444-7927

Selected Publications:

Hu X, Hou H, Bastian C, He W, Qiu S, Ge Y, Yin X, Kidd GJ, Brunet S, Trapp BD, Baltan S, Yan R. (2017) BACE1 regulates the proliferation and cellular functions of Schwann cells. Glia 65(5):712-726. PMID: 28191691; PMCID: PMC5357169

Sharoar MG, Yan R. (2017) Effects of altered RTN3 expression on BACE1 activity and Alzheimer's neuritic plaques. Rev Neurosci 28(2):145-154. PMID: 27883331

Yan R. (2016) Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Transl Neurodegener 5:13. PMID: 27418961; PMCID: PMC4944430

Yan R, Fan Q, Zhou J, Vassar R. (2016) Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer's disease. Neurosci Biobehav Rev 65:326-40. PMID: 27044452; PMCID: PMC4856578

Hu X, Fan Q, Hou H, Yan R. (2016) Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling. J Neurochem 136(2):234-49. PMID: 26465092; PMCID: PMC4833723

Sharoar MG, Shi Q, Ge Y, He W, Hu X, Perry G, Zhu X, Yan R. (2016) Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease. Mol Psychiatry 21(9):1263-71. PMID: 26619807; PMCID: PMC4887420

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

Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. (1999) Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature 402(6761):533-7. PMID: 10591213

US Patent Patent Title Issue Date First-Named Inventor
6,420,534 Alzheimer's disease secretase, APP substrates therefor, and uses thereof July 16, 2002 Mark E. Gurney
6,440,698 Alzheimer's disease secretase, APP substrates therefor, and uses therefor August 27, 2002 Mark E. Gurney
6,500,667 Aspartyl protease 2 (Asp2) antisense oligonucleotides December 31, 2002 Mark E. Gurney
6,699,671 Alzheimer's disease secretase, APP substrates therefor, and uses therefor March 2, 2004 Mark E. Gurney
6,706,485 Method of identifying agents that inhibit APP processing activity March 16, 2004 Mark E. Gurney
6,727,074 Alzheimer's disease secretase, APP substrates therefor, and uses therefor April 27, 2004 Mark E. Gurney
6,737,510 Alzheimer's disease secretase, APP substrates therefor, and uses thereof May 18, 2004 Mark E. Gurney
6,753,163 Alzheimer's disease secretase, APP substrates therefor, and uses therefor June 22, 2004 Mark E. Gurney
6,790,610 Alzheimer's disease, secretase, APP substrates therefor, and uses therefor September 14, 2004 Mark E. Gurney
6,797,487 Polynucleotides encoding alzheimer's disease secretase September 28, 2004 Mark E. Gurney
6,825,023 Alzheimer's disease secretase, APP substrates therefor, and uses therefor November 30, 2004 Mark E. Gurney
6,828,117 Alzheimer's disease secretase, APP substrates therefor, and uses therefor December 7, 2004 Mark E. Gurney
6,835,565 Alzheimer's disease secretase December 28, 2004 Mark E. Gurney
6,867,018 Alzheimer's disease secretase, APP substrates therefor, and uses thereof March 15, 2005 Mark E. Gurney
6,913,918 Alzheimer's disease secretase, APP substrates therefor, and uses therefor July 5, 2005 Mark E. Gurney
7,041,473 Alzheimer's disease secretase, APP substrates therefor, and uses thereof May 9, 2006 Mark E. Gurney
7,205,120 Substrates and assays for .beta.-secretase activity April 17, 2007 Riqiang Yan
7,368,536 Alzheimer's disease secretase, APP substrates therefor, and uses therefor May 6, 2008 Mark E. Gurney
7,375,187 Alzheimer's disease secretase, APP substrates therefor, and uses therefor May 20, 2008 Mark E. Gurney
7,378,511 Alzheimer's disease secretase, APP substrates therefor, and uses therefor May 27, 2008 Mark E. Gurney
7,803,739 Substrates and assays for .beta.-secretase September 28, 2010 Riqiang Yan
7,812,123 Alzheimer's disease secretase October 12, 2010 Mark E. Gurney
7,888,291 Substrates and assays for .beta.-secretase February 15, 2011 Riqiang Yan