Individuals with
Down syndrome (DS) acquire Alzheimer's-like
dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However,
biological mechanisms have not been discovered and there is currently limited
therapy for either DS- or AD-related
dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits,
neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice exhibit progressive loss of
norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to
memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic
neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (
DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with
DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal
neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast,
DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive
memory loss,
neuroinflammation, and
cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies.