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About My Lab
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Fellow of Canadian Academy of Health Sciences
Canada Research Chair in Alzheimer's Disease
Jack Brown and Family Professor
Director, Townsend Family Laboratories

Dept. of Psychiatry, Faculty of Medicine

Special Advisor to the President on China
The University of British Columbia

E-mail: weihong@mail.ubc.ca
Office: (604) 822-8019
Lab: (604) 822-7332, 822-7383, 822-7335

Fax: (604) 822-7756

My laboratory focuses on the molecular and cellular mechanism of Alzheimer's Disease (AD) pathogenesis.

Alzheimer's disease is the most common neurodegenerative disorder leading to dementia. It accounts for two-thirds of all cases of dementia and its prevalence increases with age. AD affects about 10% of the population over the age of 65.

Deposition of Aβ in the brain is a central pathological feature of AD. Aβ is derived from APP, a type 1 transmembrane protein. Recent molecular genetic studies have shown that four genes confer susceptibility to AD: APP gene on chromosome 21; Apo E gene on chromosome 19; Presenilin 1 (PS1) on chromosome 14; and Presenilin 2 (PS2) on chromosome 1. Autosomal dominant inheritance of AD can arise from mutations of APP or PS1 and PS2. These mutations alter the processing of APP giving rise to increased production of Aβ, or a 42 amino acid form of Aβ with a high propensity for plaque formation, implicating a role for altered APP processing in the pathogenesis of familial AD.

APP undergoes a complex set of proteolytic processing by three different enzymes: α, β and γ-secretase. In normal condition, a majority of APP is cleaved by α-secretase within the Aβ domain to generate secreted form of APP (sAPP α) and a smaller 83-residue C-terminal fragment (C83 or CTFα), and it precludes Aβ generation. Aβ is generated from APP by β-secretase (BACE1) and γ-secretase. APP is cleaved by BACE1 to generate a secreted form of APP (sAPPβ) and a 99-residue membrane-associated fragment (C99). C99 is the substrate of γ-secretase and intramembrane cleavage at the γ site generates Aβ and CTFγ fragments.

Using knockout and transgenic models, we have demonstrated that presenilins are absolutely required for γ-secretase cleavage of APP to generate Aβ and intramembrane cleavage of Notch to generate NICD. Our lab recently found that SP1 plays an important role in BACE1 gene transcription, and BACE1 is degraded by ubiquitin- proteasome pathway. My laboratory is currently working on projects to further define the role of presenilins and BACE, transcriptional regulation and Notch signal transduction in neurodegeneration. Another research area of laboratory is the molecular genetics of mental disorders.


Member of Editorial Board:

Journal of Clinical Investigation

Journal of Neurochemistry

Frontiers in Molecular Neuroscience

Journal of Molecular Neuroscience

Current Alzheimer Research


Selected Publications:

Wang Z., Sadovnick A.D., Traboulsee A.L., Ross J.P., Bernales C.Q., Encarnacion M., Yee I.M., de Lemos M., Greenwood T., Lee J.D., Wright G., Ross C.J., Zhang S., Song W., and Vilariño-Güell C. (2016). Nuclear receptor NR1H3 in familial multiple sclerosis. Neuron 90, 948-954.

Zheng L., Duan J., Duan X., Zhou W., Chen C., Li Y., Chen J., Zhou W., Wang Y., Li T., and Song W. (2016). Association of Apolipoprotein E (ApoE) polymorphism with Alzheimer's disease in Chinese population. Current Alzheimer Research 13, 912-917.

Wang J. and Song W. (2016). Regulation of LRRK2 promoter activity and gene expression by Sp1. Molecular Brain 9, 33.

Wu, Y., Zhang, S., Xu, Q., Zou, H., Zhou, W., Cai, F., Li, T. and Song, W. (2016). Regulation of global gene expression and cell proliferation by APP. Scientific Reports 6, 22460.

Zhang X., Wu Y., Duan X., Chen W., Zou H., Zhang M., Zhang S., Cai F., and Song W. (2015). Upregulation of SET expression by BACE1 and its implications in Down syndrome. Molecular Neurobiology 51, 781-790.

Zis O., Zhang S., Dorovini-Zis K., Wang L., and Song W. (2015). Hypoxia signaling regulates macrophage migration inhibitory factor (MIF) expression in stroke. Molecular Neurobiology 51, 155-167.

Dong, Z., Han, H., Li, H., Bai, Y., Wang, W., Tu, M., Peng, Y., Zhou, L., He, W., Wu, X., Tan, T., Liu, M., Wu, X., Zhou, W., Jin, W., Zhang, S., Sacktor, T.C., Li, T., Song, W. and Wang, Y.T. (2015). Activity-dependent AMPAR endocytosis is a critical process for LTP decay and memory loss. Journal of Clinical Investigation 125, 234-247.

Wu, Y., Deng, Y., Zhang, S., Luo, Y., Cai, F., Zhang, Z., Zhou, W., Li, T., and Song, W. (2015). Amyloid-β precursor protein facilitates the regulator of calcineurin 1-mediated apoptosis by downregulating proteasome subunit a type-5 and proteasome subunit β type-7. Neurobiology of Aging 36, 169-177.

Zhou, W., Li, X., Huang, D., Zhou, W., Li, T., and Song, W. (2015). No significant effect of 7,8-dihydroxyflavone on APP processing and Alzheimer-associated phenotypes. Current Alzheimer Research 12, 47-52.

Zhang, M., Cai, F., Zhang, Sh., Zhang, S., and Song, W. (2014). Overexpression of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) delays Alzheimer's progression in vivo. Scientific Reports 4, 7298.

Xiang, Y., Meng, S., Wang, J., Li, S., Liu, J., Li, H., Li, T., Song, W. and Zhou, W. (2014). Two novel DNA motifs are essential for BACE1 gene transcription. Scientific Reports 4, 6864.

Zhang, S., Zis, O., Ly, P.T.T., Wu, Y., Zhang, S., Zhang, M., Cai, F., Bucala, R., Shyu, W-C., and Song, W. (2014). Downregulation of MIF by NFκB under hypoxia accelerated neuronal loss during stroke. The FASEB Journal, 28, 4394-4407.

Shi, Y., Li, J., Chen, C., Gong, M., Chen, Y., Liu, Y., Chen, J., Li, T., and Song, W. (2014). 5-mehtyltetrahydrofolate rescues alcohol-induced neural crest cell migration abnormalities. Molecular Brain 7, 67.

Duan, X., Tong, J., Xu, Q., Wu, Y., Cai, F., Li. T., and Song, W. (2014). Upregulation of human PINK1 gene expression by NFκB signalling. Molecular Brain 7, 57.

Wu, Y., Ly, P.T.T., and Song, W. (2014). Aberrant expression of RCAN1 in Alzheimer's pathogenesis: A new molecular mechanism and a novel drug target. Molecular Neurobiology 50, 1085-1097.

Sun, X., Wu, Y., Herculano, B., and Song, W. (2014). RCAN1 overexpression exacerbates calcium overloading-induced neuronal apoptosis. PloS ONE 9, e95471.

Wang, K., Liu, S., Wang, J., Wu, Y., Cai, F., and Song, W. (2014). Transcriptional regulation of human USP24 gene expression by NF-κB. Journal of Neurochemistry 128, 818-828.

Zheng, L., Liu, H., Wang, P., Song, W. and Sun, X. (2014). Regulator of calcineurin 1 gene transcription is regulated by Nuclear factor-κB. Current Alzheimer Research 11, 156-164.

Ly PT, Wu Y, Zou H, Wang R, Zhou W, Kinoshita A, Zhang M, Yang Y, Cai F, Woodgett J, Song W. (2013). Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. Journal of Clinical Investigation 123, 224–235.

Wu Y., and Song W (2013). Regulation of RCAN1 translation and its role in oxidative stress-induced apoptosis. The FASEB Jornal 27, 208-221.

Yang, Y., Wu, Y., Zhang, S., and Song, W. (2013). High glucose promotes Aβ production by inhibiting APP degradation. PloS One 8, e69824.

Zhang, X., and Song, W. (2013). The role of APP and BACE1 trafficking in APP processing and amyloid-β generation. Alzheimer's Research & Therapy 5, 46. (Review Article)

Deng, Y., Wang, Z., Wang, R., Zhang, X., Zhang, S., Wu, Y., Staufenbiel, M., Cai, F., and Song, W. (2013). Aβ Glu11 is the major β-secretase site of BACE1 and shifting the cleavage site to Aβ Asp1 contributes to Alzheimer pathogenesis. European Journal of Neuroscience 37, 1962-1969.

Liu, X., Wang, Z., Wu, Y., Wang, J., and Song, W. (2013). BACE2 degradation mediated by the macroautophagy-lysosome pathway. European Journal of Neuroscience 37, 1970-1977.

Yang, Y. and Song, W. (2013). Molecular links between Alzheimer's disease and diabetes mellitus. Neuroscience 250, 140-150. (Review Article)

Zhang, S., Zhang, M., Cai, F., and Song, W. (2013). Biological function of Presenilin and its role in AD pathogenesis. Translational Neurodegeneration 2, 15. (Review Article)

Zhang M, Deng Y, Luo Y, Zhang S, Zou H, Cai F, Wada K, Song W. (2012). Control of BACE1 degradation and APP processing by ubiquity carboxyl-terminal hydrolyses. Journal of Neurochemistry 120, 1129-1138.

Xu Q, Guo H, Zhang X, Tang B, Cai F, Zhou W, Song W. (2012). Hypoxia regulation of ATP13A2 (PARK9) gene transcription. Journal of Neurochemistry 122, 251-259.

Sun X, Bromley-Brits K, Song W (2012). Regulation of β-site APP-cleaving enzyme 1 (BACE1) gene expression and its role in Alzheimer’s Disease. Journal of Neurochemistry
120, Suppl 1:62-70
(Invited Review).

Chen CH, Zhou W, Liu S, Deng Y, Cai F, Tone M, Tone Y, Song W (2012). Increased NF-κB signaling upregulates BACE1 expression and its therapeutic potential in Alzheimer's Disease. International Journal of Neuropsychopharmacology 15, 77-90.

Bromley-Brits K, Song W (2012). The Role of TMP21 in trafficking and amyloid-β precursor protein (APP) processing in Alzheimer's Disease. Current Alzheimer Research
9, 411-24

Wang R, Ying Z, Zhao J, Zhang Y, Wang R, Lu H, Deng Y, Song W, Qing H (2012). Lys203 and Lys382 are essential for the proteasomal degradation of BACE1. Current Alzheimer Research 9, 606-15.

Ly PTT, Song W (2011). Loss of activated CaMKII at the synapse underlies Alzheimer's disease memory loss. Journal of Neurochemistry 119, 673-675 (Invited Editorial Highlight).

Bromley-Brits K, Deng Y, Song W (2011). Morris water maze test for learning and memory deficits in Alzheimer's Disease model mice. Journal of Visualized Experiments 53, e2920,
doi: 10.3791/2920

Ly PTT, Cai F, Song W (2011). Detection of neuritic plaques in Alzheimer's Disease mouse model. Journal of Visualized Experiments 53, e2831, doi: 10.3791/2831.

Liu S, Zhang S, Bromley-Brits K, Cai F, Zhou W, Xia K, Mittelholtz J, Song W (2011). Transcriptional regulation of TMP21 by NFAT. Molecular Neurodegeneration 6, 21.

Sun X, Wu Y, Chen B, Zhang Z, Zhou W, Tong Y, Yuan J, Xia K, Gronemeyer H, Flavell RA, Song W (2011). Regulator of calcineurin 1 (RCAN1) facilitates neuronal apoptosis through caspase 3 activation. Journal of Biological Chemistry 286, 9049-9062.

Wang R, Zhang M, Zhou W, Ly PT, Cai F, Song W (2011). NF-κB signaling inhibits ubiquitin carboxyl-terminal hydrolase L1 gene expression. Journal of Neurochemistry 116, 1160-1170.

Chen B, Bromley-Brits K, He G, Cai F, Zhang X, Song W (2010). Effect of synthetic cannabinoid HU210 on memory deficits and neuropathology in Alzheimer's disease mouse model.
Current Alzheimer Research 7, 255-261.

Zhou W, Cai F, Li Y, Yang GS, O'Connor KD, Holt RA, Song W (2010). BACE1 gene promoter single-nucleotide polymorphisms in Alzheimer's disease.
Journal of Molecular Neuroscience 42, 127-133.

Liu H, Wang P, Song W, Sun X (2009). Degradation of regulator of calcineurin 1 (RCAN1) is mediated by both chaperone-mediated autophagy and ubiquitin proteasome pathways. The FASEB Journal 23, 3383-3392.

Wang L, Zis O, Ma G, Shan S, Zhang X, Wang S, Dai C, Zhao J, Lin Q, Lin S, Song W (2009). Upregulation of macrophage migration inhibitory factor (MIF) gene expression in stroke.
Stroke 40, 973-976.

Qing H, He G, Ly PTT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W (2008). Valproic acid inhibits Aβ production, neuritic plaque formation and behavioral deficits in Alzheimer's disease mouse models.
The Journal of Experimental Medicine 205, 2781-2789.

Liu S, Bromley-Brits K, Kun X, Mittelholtz J, Wang R, Song W (2008). TMP21 degradation is mediated by the ubiquitin proteasome pathway.
European Journal of Neuroscience 28, 1980-1988.

Cai F, Chen B, Zhou W, Zis O, Liu S, Holt RA, Honer WG, Song W (2008). SP1 regulates the human SNAP-25 gene expression. Journal of Neurochemistry 105, 512-523.

He G, Qing H, Ton Y, Cai F, Ishiura S, Song W (2007). Degradation of Nicastrin involves both proteasome and lysosome. Journal of Neurochemistry 101, 982-992.

Sun X, He G, Qing H, Zhou W, Dobie F, Cai F, Staufenbiel M, Huang LE, Song W (2006). Hypoxia facilitates Alzheimer's disease pathogenesis by upregulating BACE1 gene expression. Proceedings of National Academy of Sciences of the USA 103, 18727-18732.

Sun X, He G, Song W (2006). BACE2, as a novel APP θ-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome.
The FASEB Journal 20(9):1369-1376.

Sun X, Tong Y, Qing, H. Chen C-H, Song W (2006). Increased BACE1 maturation contributes to the pathogenesis of Alzheimer's disease in Down syndrome.
The FASEB Journal 20, 1361-1368.

He G, Qing H, Cai F, Kwok C, Xu H, Yu G, Bernstein A, Song W (2006).
Ubiquitin-proteasome pathway mediates degradation of APH-1.
Journal of Neurochemistry 99, 1403-12.

Zhou W, Song W (2006). Leaky scanning and reinitiation regulate BACE1 gene expression. Molecular and Cellular Biology 26(9): 3353-64.

Li Y, Zhou W, Tong Y, He G, Song W (2006). Control of APP processing and Aβ generation level by BACE1 enzymatic activity and transcription. The FASEB Journal 20(2):285-92.

Sun X, Wang Y, Qing H, Christensen MA, Liu Y, Zhou W, Tong Y, Xiao C, Huang Y, Zhang S, Liu X, Song W (2005). Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes. The FASEB Journal 19(7):739-749.

Tong Y, Zhou W, Fung V, Christensen MA, Qing H, Sun X, Song W (2005). Oxidative stress potentiates BACE1 gene expression and Aβ generation.
Journal of Neural Transmission 112(3):455-69.

Christensen MA, Zhou W, Qing H, Lehman A, Philipsen S, Song W (2004). Transcriptional regulation of BACE1, the β-amyloid precursor protein β-secretase, by Sp1.
Molecular and Cellular Biology 24(2):865-74.

Qing H, Zhou W, Christensen MA, Sun X, Tong Y, Song W (2004). Degradation of BACE by the ubiquitin-proteasome pathway. The FASEB Journal 18(13):1571-3.

Zhou W, Qing H, Tong Y, Song W (2004). BACE1 gene expression and protein degradation. Annals of the New York Academy of Sciences 1035:49-67.

Xu J, Kao SY, Lee FJ, Song W, Jin LW, Yankner BA (2002). Dopamine-dependent neurotoxicity of α-synuclein: a mechanism for selective neurodegeneration in Parkinson disease.
Nature Medicine

Song W, Yankner BA (2001). Presenilins and Notch Signaling Pathway. In: Alzheimer's Disease: Advances in Etiology, Pathogenesis and Therapeutics, Iqbal, K., Sisodia, S.S. & Winbald, B. (eds), Chapter 49, 531-539.

Zhang Z, Nadeau P, Song W, Yuan M, Donoviel D, Bernstein A, Yankner BA (2000). Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nature Cell Biology 2, 463-465.

Song W, Nadeau P, Yuan M, Yang X, Shen J, Yankner BA (1999). Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations.
Proceedings of National Academy of Sciences of the USA 96, 6959-6963.

Song W, Lahiri DK (1995). Efficient transfection of DNA by mixing cells in suspension with calcium phosphate. Nucleic Acids Research 23(17):3609-11.


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