Parallel age-associated changes in brain and plasma neuronal pentraxin receptor levels in a transgenic APP/PS1 rat model of Alzheimer's disease

Neuronal pentraxin receptor (NPR) is a synaptic protein implicated in AMPA receptor trafficking at excitatory synapses. Since glutamate neurotransmission is disrupted in Alzheimer's disease (AD), NPR levels measured from plasma represent a potential biomarker for synaptic dysfunction associated with AD. We sought to determine the relationship between AD pathology and brain and plasma NPR levels by examining age-associated NPR levels in these compartments in a transgenic APP/PS1 rat model of AD. NPR levels in cortical homogenate were similar in wild-type (Wt) and APP/PS1 rats at 3 months of age (prior to Aβ plaque deposition), but significantly increased in APP/PS1 rats by 9 and 18-20 months of age (after the onset of plaque deposition). These age-dependent differences were driven by proportional increases in NPR in membrane-associated cortical fractions. Genotype-related differences in NPR expression were also seen in the hippocampus, which exhibits significant Aβ pathology, but not in the cerebellum, which does not. Plasma analyses revealed increased levels of a 26 kDa NPR fragment in APP/PS1 rats relative to Wt rats by 18-20 months of age, which correlated with the levels of full-length NPR in cortex. Our findings indicate that cerebral accumulation of NPR and Aβ occurs with similar temporal and regional patterns in the APP/PS1 model, and suggest that a 26 kDa plasma NPR fragment may represent a peripheral biomarker of this process.