Timothy Huang, Ph.D.

Timothy Huang's Research Focus

Alzheimer's Disease, Molecular Biology
Cell Signaling, Neurobiology, Neurodegeneration, Neurogenesis, Neuron-Glia Interactions in Myelin, Proteolytic Pathways, Tyrosine Kinases, Cell Biology
Human, Mouse, Human Cell Lines, Mouse Cell Lines
Biochemistry, Cellular and Molecular Imaging, Confocal Microscopy, Electrophysiology, Mass Spectrometry, Protein-Protein Interactions, Protein-Small Molecule Interactions, Proteomics, Protein Engineering

My research is focused on identifying and characterizing mechanisms of neurodegeneration in Alzheimer's disease (AD) and other related neurodegenerative disorders, and identifying neuroprotective pathways that may be involved in slowing disease progression. Currently, my research is focused on the genetic AD risk factors SORLA (SORL1, LR11) and TREM2, which may be involved in attenuating pathogenic effects associated with cognitive decline. By implementing methods to enhance these neuroprotective pathways, we may be able to reverse neuronal and cognitive damage in AD, and possibly other associated disorders.

Timothy Huang's Research Report

There are two projects that comprise my main focus: 1) SORLA: Sortilin-related receptor with LDLR class A repeats (SOR​LA, SORL1, or LR11) is a genetic risk factor associated with Alzheimer’s disease (AD). Although SOR​LA is known to regulate trafficking of the amyloid β (Aβ) precursor protein to decrease levels of proteotoxic Aβ oligomers, whether SOR​LA can counteract synaptic dysfunction induced by Aβ oligomers remains unclear. Our work indicates that SOR​LA interacts with the EphA4 receptor tyrosine kinase and attenuates ephrinA1 ligand–induced EphA4 clustering and activation to limit downstream effects of EphA4 signaling in neurons. Consistent with these findings, SOR​LA transgenic mice, compared with WT mice, exhibit decreased EphA4 activation and redistribution to postsynaptic densities, with milder deficits in long-term potentiation and memory induced by Aβ oligomers. Importantly, we detected elevated levels of active EphA4 in human AD brains, where EphA4 activation is inversely correlated with SORLA/EphA4 association. These results demonstrate a novel role for SOR​LA as a physiological and pathological EphA4 modulator, which attenuates synaptotoxic EphA4 activation and cognitive impairment associated with Aβ-induced neurodegeneration in AD. 2) TREM2: Although ligands for TREM2 such as ApoE have been previously identified, a definitive mechanism for TREM2 in AD has not been established. We recently determined that TREM2 directly binds Aβ oligomers with nanomolar affinity and R47H mutations attenuate TREM2/Aβ interaction. TREM2 deletion impairs Aβ turnover in primary microglia, and abrogates Aβ clearance in vivo. Aβ also triggers changes in microglial membrane potential which is impaired with TREM2 deletion. Moreover, TREM2 deletion attenuates Aβ-induced microglial morphogenic changes associated with activation, and inhibits Aβ-mediated induction of proinflammatory cytokine expression. Together, these results indicate that TREM2 may have opposing neuroprotective roles in mediating microglial Aβ clearance and turnover, while concurrently transducing potentially neurotoxic Aβ-induced inflammatory signals. To further define a role for TREM2 in Aβ clearance and Aβ-mediated microglial activation/cytokine expression, we plan to exploit use of TREM2 R47H knock-in and TREM2 WT and R47H overexpression mouse models currently housed in our laboratory to determine whether impaired TREM2/Aβ interactions can impair microglial response in the presence of Aβ. This provides essential groundwork in future strategies to optimize neuroprotective TREM2 Aβ clearance while limiting Aβ-induced microglial inflammation.

Timothy Huang's Bio

Timothy Huang completed his Ph.D. at the University of Calgary (Canada) under Dr. Dallan Young, studying kinase pathways involved in mediating cell polarity in yeast. He studied mechanisms underlying actin cytoskeletal dysfunction in Alzheimer's disease at Scripps with Dr. Gary Bokoch (La Jolla), before joining Dr. Huaxi Xu's laboratory in 2012/2013.

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SORLA attenuates EphA4 signaling and amyloid β-induced neurodegeneration.

Huang TY, Zhao Y, Jiang LL, Li X, Liu Y, Sun Y, Piña-Crespo JC, Zhu B, Masliah E, Willnow TE, Pasquale EB, Xu H

J Exp Med 2017 Dec 4 ;214(12):3669-3685

SNX27 and SORLA Interact to Reduce Amyloidogenic Subcellular Distribution and Processing of Amyloid Precursor Protein.

Huang TY, Zhao Y, Li X, Wang X, Tseng IC, Thompson R, Tu S, Willnow TE, Zhang YW, Xu H

J Neurosci 2016 Jul 27 ;36(30):7996-8011

A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation.

Huang TY, Michael S, Xu T, Sarkeshik A, Moresco JJ, Yates JR 3rd, Masliah E, Bokoch GM, DerMardirossian C

Mol Biol Cell 2013 Feb ;24(3):194-209

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Multi-omic comparison of Alzheimer's variants in human ESC-derived microglia reveals convergence at APOE.

Liu T, Zhu B, Liu Y, Zhang X, Yin J, Li X, Jiang L, Hodges AP, Rosenthal SB, Zhou L, Yancey J, McQuade A, Blurton-Jones M, Tanzi RE, Huang TY, Xu H

J Exp Med 2020 Dec 7 ;217(12)

RPS23RG1 modulates tau phosphorylation and axon outgrowth through regulating p35 proteasomal degradation.

Zhao D, Zhou Y, Huo Y, Meng J, Xiao X, Han L, Zhang X, Luo H, Can D, Sun H, Huang TY, Wang X, Zhang J, Liu FR, Xu H, Zhang YW

Cell Death Differ 2021 Jan ;28(1):337-348

Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease.

Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y

Mol Neurodegener 2020 Jul 16 ;15(1):40

Soluble SORLA Enhances Neurite Outgrowth and Regeneration through Activation of the EGF Receptor/ERK Signaling Axis.

Stupack J, Xiong XP, Jiang LL, Zhang T, Zhou L, Campos A, Ranscht B, Mobley W, Pasquale EB, Xu H, Huang TY

J Neurosci 2020 Jul 29 ;40(31):5908-5921

Cyclin-Dependent Kinase 5-Dependent BAG3 Degradation Modulates Synaptic Protein Turnover.

Zhou J, Chow HM, Liu Y, Wu D, Shi M, Li J, Wen L, Gao Y, Chen G, Zhuang K, Lin H, Zhang G, Xie W, Li H, Leng L, Wang M, Zheng N, Sun H, Zhao Y, Zhang Y, Xue M, Huang TY, Bu G, Xu H, Yuan Z, Herrup K, Zhang J

Biol Psychiatry 2020 Apr 15 ;87(8):756-769

Appoptosin Mediates Lesions Induced by Oxidative Stress Through the JNK-FoxO1 Pathway.

Zhang C, Tan Z, Xie Y, Zhao Y, Huang TY, Lu Z, Luo H, Can D, Xu H, Zhang YW, Zhang X

Front Aging Neurosci 2019 ;11:243

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