Our research focuses on the molecular and cellular mechanism underlying the pathogenesis of Alzheimer’s disease. Because Sanford-Burnham has an exceptional collaborative environment, which is at the forefront of interdisciplinary research, I am confident that it will be here that new ideas and research strategies emerge. These innovations will help elucidate the insidious nature of Alzheimer’s – a devastating disease that impacts the lives of millions throughout the world.
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Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome.
Wang X, Zhao Y, Zhang X, Badie H, Zhou Y, Mu Y, Loo LS, Cai L, Thompson RC, Yang B, Chen Y, Johnson PF, Wu C, Bu G, Mobley WC, Zhang D, Gage FH, Ranscht B, Zhang YW, Lipton SA, Hong W, Xu H
Nat Med. 2013 Apr;19(4):473-80
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy.
Liu CC, Liu CC, Kanekiyo T, Xu H, Bu G
Nat Rev Neurol. 2013 Feb;9(2):106-18
Appoptosin is a novel pro-apoptotic protein and mediates cell death in neurodegeneration.
Zhang H, Zhang YW, Chen Y, Huang X, Zhou F, Wang W, Xian B, Zhang X, Masliah E, Chen Q, Han JD, Bu G, Reed JC, Liao FF, Chen YG, Xu H
J Neurosci. 2012 Oct 31;32(44):15565-76
Alzheimer's β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid.
Chen Y, Huang X, Zhang YW, Rockenstein E, Bu G, Golde TE, Masliah E, Xu H
J Neurosci. 2012 Aug 15;32(33):11390-5
Insulin signaling in sporadic Alzheimer's disease.
Liao FF, Xu H
Sci Signal. 2009;2(74):pe36
Presenilin/gamma-secretase-dependent processing of beta-amyloid precursor protein regulates EGF receptor expression.
Zhang YW, Wang R, Liu Q, Zhang H, Liao FF, Xu H
Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10613-8
Hypoxia-inducible factor 1alpha (HIF-1alpha)-mediated hypoxia increases BACE1 expression and beta-amyloid generation.
Zhang X, Zhou K, Wang R, Cui J, Lipton SA, Liao FF, Xu H, Zhang YW
J Biol Chem. 2007 Apr 13;282(15):10873-80
Chaperones increase association of tau protein with microtubules.
Dou F, Netzer WJ, Tanemura K, Li F, Hartl FU, Takashima A, Gouras GK, Greengard P, Xu H
Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):721-6
Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides.
Xu H, Gouras GK, Greenfield JP, Vincent B, Naslund J, Mazzarelli L, Fried G, Jovanovic JN, Seeger M, Relkin NR, Liao F, Checler F, Buxbaum JD, Chait BT, Thinakaran G, Sisodia SS, Wang R, Greengard P, Gandy S
Nat Med. 1998 Apr;4(4):447-51
Huaxi Xu's Research Focus
Alzheimer's Disease, Aging-Related Diseases, Neurodegenerative and Neuromuscular Diseases, Nervous System Injury, Neurological and Psychiatric Disorders, Parkinson's Disease, Stroke
Genetic, molecular/cellular and biochemical evidence strongly support a causal role of Aβ in AD pathogenesis. Therefore, inhibition of Aβ production and aggregation represent key goals in the search for AD therapies. Research efforts in the Xu laboratory address this goal by seeking to understand the molecular and cellular mechanisms underlying Aβ generation. The laboratory’s accomplishments and ongoing activities are summarized:
Huaxi Xu's Research Report
Molecular and Cellular Mechanism of Alzheimer's Disease
(AD), the most common cause of dementia in the elderly, is characterized by impaired memory and cognitive capacities. It affects 10% of individuals over 65 years of age and 50% over 85 years. Specialists estimate that the number of Americans with Alzheimer's disease (5 million today) could reach 16 million by 2050. Currently, there is no cure for AD and its symptoms can only be partially addressed.
The most prominent pathological brain lesions of AD are the senile plaques, which consist of extracellular aggregates of 40-42 amino acid-long peptides, termed β-amyloid (Aβ), and neurofibrillary tangles (NFT), which consist of the cytoskeletal protein, tau. Aβ is generated by sequential endoproteolytic processing of Amyloid Precursor Protein (APP) by β- and γ-secretases. NFT’s are associated with abnormal patterns of phosphorylation of the tau protein. The precise mechanisms by which Aβ and tau damage the brain have yet to be defined. However, diseased nerve cells often exhibit alterations in the neuronal cytoskeleton, and these cellular abnormalities in specific neuronal circuits have profound clinical consequences and thus may represent a biological substrate of dementia. Over the past ten years, molecular geneticists have identified genes that are mutated in pedigrees of early-onset, autosomal dominant forms of AD (FAD). These genes encode presenilin 1 (PS1), presenilin 2 (PS2), and APP. All FAD-linked mutations result in overproduction and accumulation of Aβ.
My research efforts focus on understanding the molecular events that underlie the pathogenesis of AD. They integrate genetic, neurobiological, molecular and cellular information to clarify the normal biology of APP and presenilins and the mechanisms by which mutant genes that alter these proteins cause AD. Our research projects investigate the proteolytic processing and trafficking of Aβ, the abnormal phosphorylation of tau and also attempt to discover novel genes and genetic pathways that affect Aβ processing. Our goal is to characterize the cellular and molecular cascade of early events that lead to the etiopathogenesis of AD, and uncover information critical for the development of rational therapeutic strategies for the treatment of this devastating disorder.
We were among the first to identify the trans-Golgi network (TGN) as the major cellular compartment for Aβ generation, and are currently continuing studies on detailed cell biological mechanisms of APP trafficking and Aβ generation within the secretory pathway and on potential cytotoxic effects of intracellular Aβ.
Aβ generation is known to be regulated by various signal transduction pathways. We were the first to demonstrate that gonadal hormones and insulin/IGF-1 regulate intracellular trafficking of APP and modulate (lower) intracellular levels of Aβ. We are now in the process of elucidating the signaling pathways mediating the effects of gonadal hormones and insulin on APP processing.
Much of our efforts go into understanding the mechanism of action and regulation of two secretase activities responsible for Aβ generation, namely, β- and γ-secretases. The latter is a multimolecular complex consisting of PS1, PEN2, APH1 and nicastrin. We identified the subcellular locations and the protein domains of components of the β-secretase complex required for its activity. We were the first to demonstrate the functions of PEN2 and APH1 in proteolytic maturation of full-length PS1, which is essential for γ-secretase activity. We anticipate that our findings will lead to a better understanding of how each component of the complex functions coordinately in maintaining γ-secretase activity, as well as lead to the identification of potential drug targets.
Strong evidence from several groups including ours suggests a role for PS1 in regulating intracellular trafficking of select proteins including APP and nicastrin. The cellular mechanism and potential physiological relevance of PS1 regulated protein trafficking remain elusive and thus are one of our main research objectives.
In collaboration with a biotechnology company, my laboratory is attempting to identify genes and genetic pathways involved in β- and γ-secretase processing of APP using the cutting-edge technology, Random Homozygous Knockout. This approach has successfully identified several candidate genes whose functional inactivation significantly inhibits γ-cleavage, Aβ production, as well as GSK3 activity. We are currently characterizing these genes while continuing to screen for new targets.
Our recent studies have demonstrated a direct binding of the PS1/γ-secretase cleaved APP intracellular fragment ACID to the EGFR promoter and revealed a novel function of APP (namely AICD) in regulating EGFR gene expression and hence the EGFR-mediated tumorigenesis. These findings put forward a novel concept that γ-secretase may function as a tumor suppressor through alterations in the EGFR pathway/signaling and underscore the limitations of targeting γ-secretase for diseases. We also identified a novel proapoptotic protein that binds to APP/AICD and are in the process of characterizing the cellular functions of this new protein in both cell and animal models.
About Huaxi Xu
Huaxi Xu earned his Ph.D. in cell biology from Albert Einstein College of Medicine in 1993 under the supervision of Dr. Dennis Shields. He conducted his postdoctoral research in the laboratory of Paul Greengard (2000 Nobel Laureate in Physiology and Medicine) at the Rockefeller University. In 1998 he was appointed Assistant Professor at the Rockefeller University. Dr. Xu was recruited to Sanford-Burnham Medical Research Institute in 2003.