ABSTRACT Individuals with Down syndrome (DS) have shortened lifespan and face severe challenges as they age. While the primary syndrome is caused by an extra copy of chromosome 21, and is present from birth, those with DS are at a much higher risk of developing sleep and metabolic disorders and more than two thirds of individuals experience cognitive decline that resembles early-onset Alzheimer's disease (AD). There is no unified mechanism or approach to treating these co-occurring conditions, which can lead to a drastic deterioration in quality of life. Published and preliminary data indicate that impaired proteostasis and aberrant activation of the proteostasis pathway, the unfolded protein response (UPR), is a biological mechanism common to AD, disrupted sleep and metabolic dysfunction. Moreover, protein folding stress can be a direct consequence of chromosome imbalance and data from humans and mice support the concept of aberrant UPR induction in DS. Thus, we propose that individuals with DS are susceptible to protein folding stress and that restoring proteostasis is a novel therapeutic approach to prevent co-occurring conditions. We posit that reducing proteostatic stress via chemical chaperone 4-phenyl butyrate (PBA) – a small saturated fatty acid that is an FDA- approved therapy for treatment of urea cycle disorders – will in turn ameliorate disturbances in sleep, metabolism, and cognition. Amyloid precursor protein (APP), a key player in familial AD, is one of the triplicated genes in DS. Overexpression and the consequent overproduction of amyloid beta (Aβ)-peptide leads to proteotoxicity that is instrumental in the early onset of AD neuropathology in the DS population. We have found that APP knockin (APPKI) mice treated with PBA display reduced proteotoxic stress and improved cognitive behavior, even when treatment was initiated after the onset of cognitive decline. Our data also indicate that PBA improves sleep quality in APPKI and normally aging mice. Moreover, several published studies indicate that PBA restores metabolic function in obese mice. Therefore, the global hypothesis of this proposal is that reduction of proteostatic stress with the FDA-approved small molecule chaperone PBA will ameliorate sleep, metabolic and behavioral deficits in a mouse model of DS. We will use the validated DS Ts65Dn mouse model that is trisomic for about two-thirds of the genes orthologous to human chromosome 21 and displays each of the relevant phenotypes to test whether PBA treatment rescues each of these co-occurring conditions. This proposal builds on a strong body of existing literature and new preliminary data supporting the potential of PBA, an FDA-approved therapy, for improving cognitive decline, sleep disturbances, and metabolic dysfunction. As these conditions co-occur in individuals with Down syndrome, this project represents a crucial first step towards developing a unified therapeutic approach.