Microglia,
the resident macrophages in the brain, are strongly implicated in the
progressive nature of AlzheimerÕs disease (AD). In response to amyloid-‰ (A‰) and neuronal damage,
microglia produce toxic factors such as cytokines and reactive oxygen species
(ROS), which are then toxic to neighboring neurons. However, traditional anti-inflammatory therapies such as
NSAIDs and generalized antioxidant therapies have largely failed in human AD
studies. The over-arching
hypothesis of our work is that the development of effective anti-inflammatory
drugs for the treatment of AD must ameliorate multiple pro-inflammatory
factors and target the most deleterious consequences of microglial
activation: NADPH oxidase
activation and ROS production.
The basis of this assertion is that microglia-derived ROS are
neurotoxic through two mechanisms:
1) extracellular ROS is directly neurotoxic; 2) intracellular ROS
function as a signaling mechanism in microglia to amplify the production of
several pro-inflammatory and neurotoxic cytokines (ex. TNF‡, PGE2, and
IL-1‰). Thus, the inhibition of
microglial ROS reduces a broad spectrum of factors responsible for neuron
damage. Microglial NADPH
oxidase is a multi-subunit enzyme complex responsible for the production of
both extracellular and intracellular ROS, making it a key factor in both the
regulation of microglial activation and associated neurotoxicity. Further, NADPH oxidase is an
essential component of microglia-mediated A‰ neurotoxicity and is upregulated
in AD, making this enzyme an ideal target for the therapeutic treatment of AD. Previously, we and others have
demonstrated that dextromethorphan (a commercially available antitussive,
morphinan compound) and apocynin (a naturally occurring, specific NADPH
oxidase inhibitor) are neuroprotective in ParkinsonÕs disease models through
NADPH oxidase inhibition. Here,
using mutant human amyloid precursor protein (hAPP) transgenic mice as an in
vivo model of AD, we will be the first to test the specific hypothesis that
NADPH oxidase inhibitors (dextromethorphan and apocynin) protect against
A‰-induced neuroinflammation, ROS, neuronal damage, and changes in behavioral
measures of learning and memory in vivo. Thus, the specific aims of this proposal are to: 1)
determine the anti-inflammatory and ROS-reducing characteristics of NADPH
oxidase inhibitors in hAPP mice; 2) characterize the neuroprotective profiles
of NADPH oxidase inhibitors in hAPP mice; 3) characterize the ability of
NADPH oxidase inhibitors to improve behavioral measures of learning and
memory in hAPP mice. The results
from this in vivo approach will establish the pre-clinical proof of concept
that targeting microglial NADPH oxidase suppresses A‰-induced
neuroinflammation and ROS in vivo, with a consequent reduction of neuronal
damage and dysfunction. Further,
the present study will identify a patented, safe, and clinically relevant
therapeutic compound (dextromethorphan) that is neuroprotective through NADPH
oxidase inhibition. Finally,
this work will establish the basis for future studies aimed at targeting
NADPH oxidase for the development of novel therapeutic compounds capable of
slowing or halting the progression of AD.