Project Summary
The effects of long-term locus coeruleus stimulation on amyloid/tau pathology, synaptic plasticity, and
memory during Alzheimer’s disease progression
Alzheimer’s disease (AD) is a neurodegenerative disease and accounts for up to 80% of all dementia
diagnoses. Despite the immense burden that AD imposes on society, there is currently no effective method to
prevent or treat AD. Severe degeneration of the locus coeruleus (LC) is a ubiquitous hallmark in AD. The LC is
the primary source of norepinephrine (NE) to the whole forebrain and regulates many aspects of normal brain
function. An aberrant form of tau is found in the LC in young healthy adults, making the LC the first region with
AD-like neuropathology in the human brain. Previous work has suggested that NE facilitates the immune-
mediated removal of Aß through regulation of microglial phagocytosis. In addition, the anti-inflammatory effect
of NE has been demonstrated in many studies. Therefore, the LC-NE system is a promising therapeutic target
in AD. However, the consequences of long-term LC stimulation during AD progression remain unknown. In this
project, using a synthesis of chemogenetic manipulation, retrograde Cre-dependent viral ablation,
immunohistology, and behavioral paradigms, we will examine the effects of long-term locus coeruleus
stimulation on amyloid/tau pathology, synaptic plasticity, and memory in Aß and tau mouse models. In Aim 1,
we will determine the extent to which long term direct LC stimulation delays the deterioration of memory
function and improves synaptic plasticity. In Aim 2, we will characterize the effects of long-term LC stimulation
on amyloid and tau pathology during AD progression. In Aim 3, we will examine the role of non-uniform LC
degeneration in structure-specific amyloid and tau pathology in the brain. This project will provide much-
needed insight about the extent to which long term LC stimulation mitigates amyloid and tau pathology and
rescues memory functions during AD progress. Such information will likely lead to the development of new
therapeutics for AD that utilize both non-invasive and invasive brain stimulation technologies to directly engage
the LC-NE system.
