ABSTRACT
Down syndrome (DS) is the most common cause of genetically determined intellectual disability in the United
States, affecting approximately 1 in 700 live births and an estimated 300,000 Americans. A close association
between DS and Alzheimer's disease (AD) has been established, and this has become a paramount concern
since improved medical care has led to increased life expectancy, with an average life span close to 60 years of
age. Individuals with DS exhibit AD neuropathological hallmarks including amyloid plaques and neurofibrillary
tangles as early as in their 30s, and the thought is that AD pathology may develop early in life, and therefore
could be the target for neuroprotection therapies. However, little is known about mechanisms for the
development of memory impairment and AD pathology in those with DS.
Noradrenergic locus coeruleus (LC-NE) neurons degenerate early in AD and in DS-AD, and enhancement of the
NE transmitter system using existing NE-enhancing drugs could lead to novel treatment options for dementia in
DS with AD. In addition, recent studies have shown that the earliest Tau pathology is present in LC-NE neurons
in AD, suggesting an early involvement of AD pathology in this neuronal population. However, specific effects of
LC-NE firing rates and/or NE release in target regions have not been explored to date. Further, LC-NE
innervation regulates glial activity, blood-brain barrier integrity and overall blood flow in the brain. It is possible
that the elevated neuroinflammation and vascular microbleeds observed in humans with DS might be associated
with the LC-NE degeneration, but this has not been examined. We wish to utilize two different mouse models of
DS, Ts65Dn and Dp16 mice, as well as a novel chemogenetic tools, Designer Receptors (DREADDs) and
neuron-derived exosomes to examine the role of LC-NE signaling and Tau seeding originating in the LC for AD
pathology in DS. DREADDs can be used to regulate the activity of discrete neuronal populations in brain. We
have recently shown that excitatory DREADDs injected directly into the LC gave rise to improved cognition in
DS mice, and that inhibitory DREADDs aggravated neuroinflammation and cognitive loss in younger DS mice.
However, biological mechanisms for these effects have not yet been explored. The overall hypothesis for this
research program is that LC-NE loss of activity contributes to neuropathology, vascular changes and memory
loss in DS. We propose to utilize novel technology, DREADDs, to “turn on” and “turn off” LC-NE firing rates and
explore effects of this on NE release, cognitive performance, and glial activation in the hippocampus (Aim 1).
Further, we will explore whether turning off LC-NE firing using DREADD technology alters BBB permeability and
vascular morphology in DS mice (Aim 2). Finally, we will utilize neuron-derived exosomes from DS, DS-AD, or
controls injected directly into the LC-NE area in DS mice to examine effects of tangle formation on LC-NE firing
rates, NE release in the hippocampus, and spread of Tau pathology to other brain regions (Aim 3).