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).
Down syndrome (DS) is a genetic condition that occurs in 1 out of 700 births with more than 350,000 Americans affected. Alzheimer's disease (AD) occurs with high penetrance in DS and few treatment options are available. Data obtained from this project can translate to treatment potentials in AD in the general population and are focused on noradrenergic systems and inflammation.
