PROJECTIVE SUMMARY
Alzheimer’s disease (AD), characterized by abnormal accumulation of amyloid plaques and neurofibrillary
tangles within the brain, is the most common form of dementia for adults aged 65 and up and the 7th leading
cause of death worldwide. Despite initial diagnoses of AD occurring over a century ago, effective clinical
therapies to prevent or treat disease progression are currently lacking. The locus coeruleus (LC), an important
brainstem nuclei which acts as the primary source of norepinephrine (NE) throughout the brain, has been
identified as one of the earliest structures to deteriorate in AD. LC degeneration is strongly correlated with
severity of cognitive decline, suggesting strategies to preserve or enhance LC function offer significant
therapeutic potential. Furthermore, NE potentiates established anti-inflammatory properties and is known to
induce microglia phagocytosis and clearance of amyloid in AD. Therefore, promoting NE release via LC
stimulation is an emerging strategy to alleviate neuropathology and cognitive deficits in AD. However, the
molecular and cellular processes which govern the potential therapeutic effects of the LC-NE system during AD
progression remain unknown. This K00 research strategy proposes a multi-modal approach involving gene
editing, intravital imaging, electrophysiology, behavioral training, and single cell sequencing to reveal the
functional role of cell-type and sub-type specific noradrenergic receptors during LC stimulation in AD. In Aim 1,
a baseline will be established determining the extent in which long-term LC stimulation reduces
neuroinflammation, amyloid/tau burden, and cognitive impairment in two different rodent models of AD. In Aim 2
and 3, gene editing will be used to interfere with sub-type specific noradrenergic receptors in astrocytes and
microglia, respectively, to understand both cell-type and sub-type specific contributions of noradrenergic
receptors on therapeutic outcomes in neuropathology and cognitive performance following long-term LC
stimulation in AD. Neuroinflammatory profiles within individual cell populations will be assessed using single cell
RNA sequencing while morphological and functional changes will be tracked longitudinally using two-photon
microscopy. Alterations in disease neuropathology following long-term LC stimulation will be compared to
changes in neuronal electrophysiology and cognitive performance over time. Ultimately, the outcomes of this
proposal will overcome significant knowledge barriers surrounding how LC stimulation rescues AD symptoms
and highlight novel biological targets to enhance therapeutic efficacy of neuromodulatory drugs and devices for
disease therapy.