Targeting tau pathology with copper-modulating strategies in Alzheimers disease

Alzheimer's disease is associated with two main types of abnormalities in the brain,
plaques and neurofibrillary tangles. Our lab, like most labs trying to develop
new treatments for Alzheimer's disease, has focused on the plaques up to this point.
Based on a number of recently completed studies, we are proposing to shift our
focus to the neurofibrillary tangles. Based on preliminary evidence that brain levels
of copper affect the development of neurofibrillary tangles, the hypothesis is
specifically focused on the relationship between copper and tangles.
OBJECTIVES: 1) We will determine if copper can act directly on the precursor of the
tangle, a brain protein named tau. 2) We will determine if the individuals baseline
level of copper affects their ability to respond to the treatment, 3) we will determine
if copper has an effect on the type of tau associated with sporadic Alzheimer's
disease or the type of tau associated with some forms of hereditary frontotemporal
dementia. 4) we will determine if a treatment which prevents protein misfolding
can be used to enhance the effects of copper modulating therapy.
PLAN: Experiments will be conducted in mice which are genetically engineered to
express aspects of Alzheimer's pathology. Mice will be given treatments that raise
or lower brain copper levels, and the effects on tangle pathology and memory
function will be measured.
METHODS: Standardized tests of mouse behavior, brain concentrations of disease-
associated proteins, tests of cognitive function.
FINDINGS TO DATE: Copper seems to increase tau phosphorylation and worsen
memory in mice with neurofibrillary tangles.
CLINICAL RELEVANCE: These experiments are designed to lead to clinical trials of
copper-lowering treatment for Alzheimer's disease and related dementias.
RELEVANCE TO THE VA'S MISSION: Development of safe, effective therapies for
Alzheimer's disease and frontotemporal dementia is within the VA mission. Since
neurofibrillary tangles are also seen in traumatic brain injury (TBI), this work may
have additional relevance to the VA mission.