I am a post-doctoral scientist working in research administration at Dana-Farber Cancer Institute in Boston, MA. My background is in cell biology and immunology, with an interest in cell signalling.
Alzheimer's disease (AD) is increasing in prevalence with the aging population. Deposition of amy... more Alzheimer's disease (AD) is increasing in prevalence with the aging population. Deposition of amyloid-β (Aβ) in the brain of AD patients is a hallmark of the disease and is associated with increased microglial numbers and activation state. The interaction of microglia with Aβ appears to play a dichotomous role in AD pathogenesis. On one hand, microglia can phagocytose and clear Aβ, but binding of microglia to Aβ also increases their ability to produce inflammatory cytokines, chemokines, and neurotoxic reactive oxygen species (ROS). Scavenger receptors, a group of evolutionally conserved proteins expressed on the surface of microglia act as receptors for Aβ. Of particular interest are SCARA-1 (scavenger receptor A-1), CD36, and RAGE (receptor for advanced glycation end products). SCARA-1 appears to be involved in the clearance of Aβ, while CD36 and RAGE are involved in activation of microglia by Aβ. In this review, we discuss the roles of various scavenger receptors in the interaction of microglia with Aβ and propose that these receptors play complementary, nonredundant functions in the development of AD pathology. We also discuss potential therapeutic applications for these receptors in AD.
(AD) is deposition of amyloid β (Aβ) in
the brain. Aβ binds to microglia via a receptor
complex t... more (AD) is deposition of amyloid β (Aβ) in the brain. Aβ binds to microglia via a receptor complex that includes CD36 leading to production of pro-inflammatory cytokines and neurotoxic reactive oxygen species (ROS), and subsequent neurodegeneration. Interruption of Aβ binding to CD36 is a potential therapeutic strategy for AD. To identify pharmacologic inhibitors of Aβ binding to CD36, we developed a 384-well plate assay for binding of fluorescently labeled Aβ to Chinese hamster ovary cells stably expressing human CD36 (CHO-CD36) and screened an FDA-approved compound library. The assay was optimized based on the cells’ tolerance to DMSO, Aβ concentration, time required for Aβ binding ratio. Using this assay, we identified four compounds as potential inhibitors of Aβ binding to CD36. These compounds were ursolic acid, ellipticine, zoxazolamine and homomoschatoline. Of these compounds, only ursolic acid– a naturally occurring pentacyclic triterpenoid –successfully inhibited binding of Aβ to CHO-CD36 cells in a dose dependent manner. The ursolic acid effect reached a plateau at ~20 μM, with a maximal inhibition of 64%. Ursolic acid also blocked binding of Aβ to microglial cells and subsequent ROS production. Our data indicate that cell-based high-content screening of small molecule libraries for their ability to block binding of Aβ to its receptors is a useful tool to identify novel inhibitors of receptors involved in AD pathogenesis. Our data also suggest that ursolic acid is a potential therapeutic agent for AD via its ability to block Aβ-CD36 interactions
In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized lo... more In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-β triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-β trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-β stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events.
Alzheimer's disease (AD) is increasing in prevalence with the aging population. Deposition of amy... more Alzheimer's disease (AD) is increasing in prevalence with the aging population. Deposition of amyloid-β (Aβ) in the brain of AD patients is a hallmark of the disease and is associated with increased microglial numbers and activation state. The interaction of microglia with Aβ appears to play a dichotomous role in AD pathogenesis. On one hand, microglia can phagocytose and clear Aβ, but binding of microglia to Aβ also increases their ability to produce inflammatory cytokines, chemokines, and neurotoxic reactive oxygen species (ROS). Scavenger receptors, a group of evolutionally conserved proteins expressed on the surface of microglia act as receptors for Aβ. Of particular interest are SCARA-1 (scavenger receptor A-1), CD36, and RAGE (receptor for advanced glycation end products). SCARA-1 appears to be involved in the clearance of Aβ, while CD36 and RAGE are involved in activation of microglia by Aβ. In this review, we discuss the roles of various scavenger receptors in the interaction of microglia with Aβ and propose that these receptors play complementary, nonredundant functions in the development of AD pathology. We also discuss potential therapeutic applications for these receptors in AD.
(AD) is deposition of amyloid β (Aβ) in
the brain. Aβ binds to microglia via a receptor
complex t... more (AD) is deposition of amyloid β (Aβ) in the brain. Aβ binds to microglia via a receptor complex that includes CD36 leading to production of pro-inflammatory cytokines and neurotoxic reactive oxygen species (ROS), and subsequent neurodegeneration. Interruption of Aβ binding to CD36 is a potential therapeutic strategy for AD. To identify pharmacologic inhibitors of Aβ binding to CD36, we developed a 384-well plate assay for binding of fluorescently labeled Aβ to Chinese hamster ovary cells stably expressing human CD36 (CHO-CD36) and screened an FDA-approved compound library. The assay was optimized based on the cells’ tolerance to DMSO, Aβ concentration, time required for Aβ binding ratio. Using this assay, we identified four compounds as potential inhibitors of Aβ binding to CD36. These compounds were ursolic acid, ellipticine, zoxazolamine and homomoschatoline. Of these compounds, only ursolic acid– a naturally occurring pentacyclic triterpenoid –successfully inhibited binding of Aβ to CHO-CD36 cells in a dose dependent manner. The ursolic acid effect reached a plateau at ~20 μM, with a maximal inhibition of 64%. Ursolic acid also blocked binding of Aβ to microglial cells and subsequent ROS production. Our data indicate that cell-based high-content screening of small molecule libraries for their ability to block binding of Aβ to its receptors is a useful tool to identify novel inhibitors of receptors involved in AD pathogenesis. Our data also suggest that ursolic acid is a potential therapeutic agent for AD via its ability to block Aβ-CD36 interactions
In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized lo... more In atherosclerosis and Alzheimer's disease, deposition of the altered self components oxidized low-density lipoprotein (LDL) and amyloid-β triggers a protracted sterile inflammatory response. Although chronic stimulation of the innate immune system is believed to underlie the pathology of these diseases, the molecular mechanisms of activation remain unclear. Here we show that oxidized LDL and amyloid-β trigger inflammatory signaling through a heterodimer of Toll-like receptors 4 and 6. Assembly of this newly identified heterodimer is regulated by signals from the scavenger receptor CD36, a common receptor for these disparate ligands. Our results identify CD36-TLR4-TLR6 activation as a common molecular mechanism by which atherogenic lipids and amyloid-β stimulate sterile inflammation and suggest a new model of TLR heterodimerization triggered by coreceptor signaling events.
Uploads
Books by Kim Wilkinson
Papers by Kim Wilkinson
the brain. Aβ binds to microglia via a receptor
complex that includes CD36 leading to
production of pro-inflammatory cytokines and
neurotoxic reactive oxygen species (ROS), and
subsequent neurodegeneration. Interruption of
Aβ binding to CD36 is a potential therapeutic
strategy for AD. To identify pharmacologic
inhibitors of Aβ binding to CD36, we developed
a 384-well plate assay for binding of
fluorescently labeled Aβ to Chinese hamster
ovary cells stably expressing human CD36
(CHO-CD36) and screened an FDA-approved
compound library. The assay was optimized
based on the cells’ tolerance to DMSO, Aβ
concentration, time required for Aβ binding ratio. Using this assay, we identified four
compounds as potential inhibitors of Aβ
binding to CD36. These compounds were
ursolic acid, ellipticine, zoxazolamine and
homomoschatoline. Of these compounds, only
ursolic acid– a naturally occurring pentacyclic
triterpenoid –successfully inhibited binding of
Aβ to CHO-CD36 cells in a dose dependent
manner. The ursolic acid effect reached a
plateau at ~20 μM, with a maximal inhibition
of 64%. Ursolic acid also blocked binding of Aβ
to microglial cells and subsequent ROS
production. Our data indicate that cell-based
high-content screening of small molecule
libraries for their ability to block binding of Aβ
to its receptors is a useful tool to identify novel
inhibitors of receptors involved in AD
pathogenesis. Our data also suggest that ursolic
acid is a potential therapeutic agent for AD via
its ability to block Aβ-CD36 interactions
the brain. Aβ binds to microglia via a receptor
complex that includes CD36 leading to
production of pro-inflammatory cytokines and
neurotoxic reactive oxygen species (ROS), and
subsequent neurodegeneration. Interruption of
Aβ binding to CD36 is a potential therapeutic
strategy for AD. To identify pharmacologic
inhibitors of Aβ binding to CD36, we developed
a 384-well plate assay for binding of
fluorescently labeled Aβ to Chinese hamster
ovary cells stably expressing human CD36
(CHO-CD36) and screened an FDA-approved
compound library. The assay was optimized
based on the cells’ tolerance to DMSO, Aβ
concentration, time required for Aβ binding ratio. Using this assay, we identified four
compounds as potential inhibitors of Aβ
binding to CD36. These compounds were
ursolic acid, ellipticine, zoxazolamine and
homomoschatoline. Of these compounds, only
ursolic acid– a naturally occurring pentacyclic
triterpenoid –successfully inhibited binding of
Aβ to CHO-CD36 cells in a dose dependent
manner. The ursolic acid effect reached a
plateau at ~20 μM, with a maximal inhibition
of 64%. Ursolic acid also blocked binding of Aβ
to microglial cells and subsequent ROS
production. Our data indicate that cell-based
high-content screening of small molecule
libraries for their ability to block binding of Aβ
to its receptors is a useful tool to identify novel
inhibitors of receptors involved in AD
pathogenesis. Our data also suggest that ursolic
acid is a potential therapeutic agent for AD via
its ability to block Aβ-CD36 interactions