The effects of long-term locus coeruleus stimulation on amyloid/tau pathology, synaptic plasticity, and memory during Alzheimer's disease progression

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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 Aβ 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 Aβ 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.